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Jacob J, Anami Y, High PC, Liang Z, Subramanian S, Ghosh SC, AghaAmiri S, Guernsey-Biddle C, Tran H, Rowe J, Azhdarinia A, Tsuchikama K, Carmon KS. Antibody-Drug Conjugates Targeting the EGFR Ligand Epiregulin Elicit Robust Antitumor Activity in Colorectal Cancer. Cancer Res 2025; 85:973-986. [PMID: 39693606 PMCID: PMC11875910 DOI: 10.1158/0008-5472.can-24-0798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2024] [Revised: 10/19/2024] [Accepted: 12/11/2024] [Indexed: 12/20/2024]
Abstract
As colorectal cancer remains a leading cause of cancer-related death, identifying therapeutic targets and approaches is essential to improve patient outcomes. The EGFR ligand epiregulin (EREG) is highly expressed in RAS wild-type (WT) and mutant colorectal cancer, with minimal expression in normal tissues, making it an attractive target for antibody-drug conjugate (ADC) development. In this study, we produced and purified an EREG mAb, H231, which had high specificity and affinity for human and mouse EREG. H231 also internalized to lysosomes, which is important for ADC payload release. ImmunoPET and ex vivo biodistribution studies showed significant tumor uptake of zirconium-89-labeled H231, with minimal uptake in normal tissues. H231 was conjugated to either cleavable dipeptide or tripeptide chemical linkers attached to the DNA-alkylating payload duocarmycin DM, and the cytotoxicity of EREG ADCs was assessed in a panel of colorectal cancer cell lines. EREG ADCs incorporating tripeptide linkers demonstrated the highest potency in EREG-expressing colorectal cancer cells irrespective of RAS mutations. Preclinical safety and efficacy studies showed that EREG ADCs were well tolerated, neutralized EGFR pathway activity, caused significant tumor growth inhibition or regression, and increased survival in colorectal cancer cell line and patient-derived xenograft models. These data suggest that EREG is a promising target for the development of ADCs for treating colorectal cancer and other cancer types that express high levels of EREG. Although the efficacy of clinically approved anti-EGFR mAbs is largely limited by RAS mutational status, EREG ADCs may show promise for both RAS mutant and WT patients, thus improving existing treatment options. Significance: EREG-targeting antibody-drug conjugates demonstrate acceptable safety and robust therapeutic efficacy in RAS mutant and wild-type colorectal cancer, suggesting their potential as an alternative to EGFR-targeted therapy to benefit a broader patient population.
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Affiliation(s)
- Joan Jacob
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Yasuaki Anami
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Peyton C. High
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Zhengdong Liang
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Shraddha Subramanian
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Sukhen C. Ghosh
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Solmaz AghaAmiri
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Cara Guernsey-Biddle
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Ha Tran
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Julie Rowe
- Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Ali Azhdarinia
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Kyoji Tsuchikama
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Kendra S. Carmon
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
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He Y, Liu F, Li Q, Jiang Z. Identification of cuproptosis and ferroptosis-related subtypes and development of a prognostic signature in colon cancer. PLoS One 2025; 20:e0307013. [PMID: 39883700 PMCID: PMC11781745 DOI: 10.1371/journal.pone.0307013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Accepted: 12/25/2024] [Indexed: 02/01/2025] Open
Abstract
Colon cancer, as a highly prevalent malignant tumor globally, poses a significant threat to human health. In recent years, ferroptosis and cuproptosis, as two novel forms of cell death, have attracted widespread attention for their potential roles in the development and treatment of colon cancer. However, the investigation into the subtypes and their impact on the survival of colon cancer patients remains understudied. In this study, utilizing data from TCGA and GEO databases, we examined the expression differences of ferroptosis and cuproptosis-related genes in colon cancer and identified two subtypes. Through functional analysis and bioinformatics methods, we elucidated pathway differences and biological characteristics between these two subtypes. By leveraging differential genes between the two subtypes, we constructed a prognostic model using univariate Cox regression and multivariate Cox regression analysis as well as LASSO regression analysis. Further survival analysis and receiver operating characteristic curve analysis demonstrated the model's high accuracy. To enhance its clinical utility, we evaluated the clinical significance of the model and constructed a nomogram, significantly improving the predictive ability of the model and providing a new tool for prognostic assessment of colon cancer patients. Subsequently, through immune-related analysis, we revealed differences in immune cell infiltration and immune function between high- and low-risk groups. Further analysis of the relationship between the model and immune cells and functions revealed potential therapeutic targets. Drug sensitivity analysis revealed associations between the expression of model-related genes and drug sensitivity, suggesting their involvement in tumor resistance through certain mechanisms. AZD8055_1059, Bortezomib_1191, Dihydrorotenone_1827, and MG-132_1862 were more sensitive in the high-risk group. Finally, we analyzed differential expression of model-related genes between tumor tissues and normal tissues, validated through real-time quantitative PCR and immunohistochemistry. In summary, our study provides a relatively accurate prognostic tool for colon cancer patients, offering guidance for treatment selection and indicating the potential of immunotherapy in colon cancer.
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Affiliation(s)
- Yinghao He
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Fuqiang Liu
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
- Department of Gastroenterology, The People’s Hospital of Jianyang City, Jianyang, Sichuan Province, China
| | - Qingshu Li
- Department of Pathology, College of Basic Medicine, Chongqing Medical University, Chongqing, China
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, China
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zheng Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Jacob J, Anami Y, High P, Liang Z, Subramanian S, Ghosh SC, AghaAmiri S, Guernsey-Biddle C, Tran H, Rowe JH, Azhdarinia A, Tsuchikama K, Carmon KS. Antibody-Drug Conjugates Targeting the EGFR Ligand Epiregulin Elicit Robust Anti-Tumor Activity in Colorectal Cancer. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.02.20.581056. [PMID: 39605519 PMCID: PMC11601497 DOI: 10.1101/2024.02.20.581056] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/29/2024]
Abstract
As colorectal cancer (CRC) remains a leading cause of cancer-related death, identifying therapeutic targets and approaches is essential to improve patient outcomes. The EGFR ligand epiregulin (EREG) is highly expressed in RAS wildtype and mutant CRC with minimal expression in normal tissues, making it an attractive target for antibody-drug conjugate (ADC) development. In this study, we produced and purified an EREG monoclonal antibody (mAb), H231, that had high specificity and affinity for human and mouse EREG. H231 also internalized to lysosomes, which is important for ADC payload release. ImmunoPET and ex vivo biodistribution studies showed significant tumor uptake of 89Zr-labeled H231 with minimal uptake in normal tissues. H231 was conjugated to either cleavable dipeptide or tripeptide chemical linkers attached to the DNA-alkylating payload duocarmycin DM, and cytotoxicity of EREG ADCs was assessed in a panel of CRC cell lines. EREG ADCs incorporating tripeptide linkers demonstrated the highest potency in EREG-expressing CRC cells irrespective of RAS mutations. Preclinical safety and efficacy studies showed EREG ADCs were well-tolerated, neutralized EGFR pathway activity, caused significant tumor growth inhibition or regression, and increased survival in CRC cell line and patient-derived xenograft models. These data suggest EREG is a promising target for the development of ADCs for treating CRC and other cancer types that express high levels of EREG. While the efficacy of clinically approved anti-EGFR mAbs are largely limited by RAS mutational status, EREG ADCs may show promise for both RAS mutant and wildtype patients, thus improving existing treatment options.
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Affiliation(s)
- Joan Jacob
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Yasuaki Anami
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Peyton High
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Zhengdong Liang
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Shraddha Subramanian
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Sukhen C. Ghosh
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Solmaz AghaAmiri
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Cara Guernsey-Biddle
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Ha Tran
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
- The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA
| | - Julie H. Rowe
- Department of Internal Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX
| | - Ali Azhdarinia
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Kyoji Tsuchikama
- Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
| | - Kendra S. Carmon
- Center for Translational Cancer Research, The Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX
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Lee HM, Saw AK, Morris VK, Napolitano S, Bristow C, Srinivasan S, Peoples M, Sorokin A, Kanikarla P, Schulz J, Singh AK, Terranova C, Coker O, Jain A, Kopetz S, Rai K. Epigenome Reprogramming Through H3K27 and H3K4 Trimethylation as a Resistance Mechanism to DNA Methylation Inhibition in BRAFV600E-Mutated Colorectal Cancer. Clin Cancer Res 2024; 30:5166-5179. [PMID: 39269307 PMCID: PMC11829253 DOI: 10.1158/1078-0432.ccr-24-1166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 07/22/2024] [Accepted: 09/11/2024] [Indexed: 09/15/2024]
Abstract
PURPOSE BRAFV600E-mutated colorectal cancer exhibits a strong correlation with DNA hypermethylation, suggesting that this subgroup of tumors presents unique epigenomic phenotypes. Nonetheless, 5-azacitidine, which inhibits DNA methyltransferase activity, is not efficacious in BRAFV600E colorectal cancer in vivo. EXPERIMENTAL DESIGN We randomized and treated mice implanted with patient-derived tumor xenografts harboring BRAFV600E mutation with control, 5-azacitidine, vemurafenib (BRAF inhibitor), or the combination. Comprehensive epigenomic profiling was conducted on control and 5-azacitidine-treated tumor samples, including DNA methylation, histone modifications, chromatin accessibility, and gene expression. Combinations of epigenetic agents were explored in preclinical BRAFV600E colorectal cancer models. RESULTS A profound reduction of DNA methylation levels upon 5-azacitidine treatment was confirmed, however, transcriptional repression was not relieved. This study unbiasedly explored the adaptive engagement of other epigenomic modifications upon 5-azacitidine treatment. A loss of histone acetylation and a gain of histone methylations, including H3K27 and H3K4 trimethylation, were observed around these hypomethylated regions, suggesting the involvement of polycomb repressive complex (PRC) activity around the genome with loss of DNA methylation, therefore maintaining the repression of key tumor-suppressor genes. Combined inhibition of PRC activity through EZH2 inhibition with 5-azacitidine treatment additively improved efficacies in BRAFV600E colorectal cancer cells. CONCLUSIONS In conclusion, DNA hypomethylation by 5-azacitidine exhibits a close association with H3K27me3 and PRC activity in BRAFV600E colorectal cancer, and simultaneous blockade of DNA methyltransferase and EZH2 holds promise as a potential therapeutic strategy for patients with BRAFV600E-mutated colorectal cancer.
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Affiliation(s)
- Hey Min Lee
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ajay Kumar Saw
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Van K. Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Stefania Napolitano
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christopher Bristow
- TRACTION platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Sanjana Srinivasan
- TRACTION platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Micheal Peoples
- TRACTION platform, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alexey Sorokin
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Preeti Kanikarla
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Jonathan Schulz
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Anand K Singh
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Christopher Terranova
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Oluwadara Coker
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Abhinav Jain
- Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Kunal Rai
- Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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Wang C, Zhao Y, Zhang S, Du M, He G, Tan S, Li H, Zhang D, Cheng L. Single-cell RNA sequencing reveals the heterogeneity of MYH11+ tumour-associated fibroblasts between left-sided and right-sided colorectal cancer. J Cell Mol Med 2024; 28:e70102. [PMID: 39294858 PMCID: PMC11410558 DOI: 10.1111/jcmm.70102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Revised: 09/03/2024] [Accepted: 09/09/2024] [Indexed: 09/21/2024] Open
Abstract
Colorectal cancer (CRC) exhibits considerable heterogeneity on tumour location. However, there is still a lack of comprehensive annotation regarding the characteristics and differences between the left-sided (L-CRC) and right-sided (R-CRC) CRC. Here, we performed single-cell RNA sequencing (scRNA-seq) on immune and stromal cells from 12 L-CRC and 10 R-CRC patients. We found that L-CRC exhibited stronger tumour invasion and poor prognosis compared with R-CRC. In addition, functional enrichment analysis of a normal cohort showed that fibroblasts of left colon are associated with tumour-related pathways. This suggested that the heterogeneity observed in both L-CRC and R-CRC may be influenced by the specific location within the colon itself. Further, we identified a potentially novel MYH11+ cancer-associated fibroblast (CAF) subset predominantly enriched in L-CRC. Moreover, we found that MYH11+ CAFs may promote tumour migration via interacting with macrophages, and was associated with poor prognosis in CRC. In summary, our study revealed the crucial role of MYH11+ CAFs in predicting a poor prognosis, thereby contributing valuable insights to the exploration of heterogeneity in L-CRC and R-CRC.
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Affiliation(s)
- Chao Wang
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Yue Zhao
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Sainan Zhang
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Meiyu Du
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Guanzhi He
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Senwei Tan
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Hailong Li
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
| | - Duoyi Zhang
- The 2nd Affiliated Hospital of Harbin Medical University, Harbin Medical UniversityHarbinHeilongjiangChina
| | - Liang Cheng
- College of Bioinformatics Science and TechnologyHarbin Medical UniversityHarbinHeilongjiangChina
- NHC Key Laboratory of Molecular Probe and Targeted Diagnosis and TherapyHarbin Medical UniversityHarbinHeilongjiangChina
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Ouchi K, Takahashi S, Sasaki K, Yoshida Y, Taniguchi S, Kasahara Y, Komine K, Imai H, Saijo K, Shirota H, Takahashi M, Ishioka C. Genome-wide DNA methylation status is a predictor of the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer: Translational research of the EPIC trial. Int J Colorectal Dis 2024; 39:89. [PMID: 38862615 PMCID: PMC11166830 DOI: 10.1007/s00384-024-04659-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/26/2024] [Indexed: 06/13/2024]
Abstract
PURPOSE The genome-wide DNA methylation status (GWMS) predicts of therapeutic response to anti-epidermal growth factor receptor (EGFR) antibodies in treating metastatic colorectal cancer. We verified the significance of GWMS as a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer. METHODS Clinical data were obtained from a prospective trial database, and a genome-wide DNA methylation analysis was performed. GWMS was classified into high-methylated colorectal cancer (HMCC) and low-methylated colorectal cancer (LMCC). The patients were divided into subgroups according to the treatment arm (cetuximab plus irinotecan or irinotecan alone) and GWMS, and the clinical outcomes were compared between the subgroups. RESULTS Of the 112 patients, 58 (51.8%) were in the cetuximab plus irinotecan arm, and 54 (48.2%) were in the irinotecan arm; 47 (42.0%) were in the HMCC, and 65 (58.0%) were in the LMCC group regarding GWMS. Compared with the LMCC group, the progression-free survival (PFS) was significantly shortened in the HMCC group in the cetuximab plus irinotecan arm (median 1.4 vs. 4.1 months, p = 0.001, hazard ratio = 2.56), whereas no significant differences were observed in the irinotecan arm. A multivariate analysis showed that GWMS was an independent predictor of PFS and overall survival (OS) in the cetuximab plus irinotecan arm (p = 0.002, p = 0.005, respectively), whereas GWMS did not contribute to either PFS or OS in the irinotecan arm. CONCLUSIONS GWMS was a predictive factor for the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer.
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Affiliation(s)
- Kota Ouchi
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Shin Takahashi
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Keiju Sasaki
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Yuya Yoshida
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Sakura Taniguchi
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Yuki Kasahara
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Keigo Komine
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Hiroo Imai
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Ken Saijo
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Hidekazu Shirota
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Masanobu Takahashi
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
- Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan
| | - Chikashi Ishioka
- Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan.
- Department of Clinical Oncology, Graduate School of Medicine, Tohoku University, Miyagi, Japan. 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan.
- Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan 4-1 Seiryo-Machi, Aobaku, Sendai, Miyagi, 980-8575, Japan.
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7
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Shen C, Fan X, Mao Y, Jiang J. Amphiregulin in lung diseases: A review. Medicine (Baltimore) 2024; 103:e37292. [PMID: 38394508 PMCID: PMC10883632 DOI: 10.1097/md.0000000000037292] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 12/14/2023] [Accepted: 01/26/2024] [Indexed: 02/25/2024] Open
Abstract
Amphiregulin is a member of the EGFR family, which is involved in many physiological and pathological processes through its binding with EGFR. Studies have found that amphiregulin plays an important role in the occurrence and development of lung diseases. This paper mainly reviews the structure and function of amphiregulin and focuses on the important role of amphiregulin in lung diseases.
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Affiliation(s)
- Chao Shen
- Department of Pediatrics, Linping Branch, the Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Xiaoping Fan
- Department of Pediatrics, Linping Branch, the Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Yueyan Mao
- Department of Pediatrics, Linping Branch, the Second Affiliated Hospital of Zhejiang University, Hangzhou, China
| | - Junsheng Jiang
- Department of Pediatrics, Linping Branch, the Second Affiliated Hospital of Zhejiang University, Hangzhou, China
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8
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Radak M, Ghamari N, Fallahi H. Identification of common factors among fibrosarcoma, rhabdomyosarcoma, and osteosarcoma by network analysis. Biosystems 2024; 235:105093. [PMID: 38052344 DOI: 10.1016/j.biosystems.2023.105093] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Revised: 11/13/2023] [Accepted: 11/23/2023] [Indexed: 12/07/2023]
Abstract
Sarcoma cancers are uncommon malignant tumors, and there are many subgroups, including fibrosarcoma (FS), which mainly affects middle-aged and older adults in deep soft tissues. Rhabdomyosarcoma (RMS), on the other hand, is the most common soft-tissue sarcoma in children and is located in the head and neck area. Osteosarcomas (OS) is the predominant form of primary bone cancer among young adults, primarily resulting from sporadically random mutations. This frequently results in the dissemination of cancer cells to the lungs, commonly known as metastasis. Mesodermal cells are the origin of sarcoma cancers. In this study, a rather radical approach has been applied. Instead of comparing homogenous cancer types, we focus on three main subtypes of sarcoma: fibrosarcoma, rhabdomyosarcoma, and osteosarcoma, and compare their gene expression with normal cell groups to identify the differentially expressed genes (DEGs). Next, by applying protein-protein interaction (PPI) network analysis, we determine the hub genes and crucial factors, such as transcription factors (TFs), affected by these types of cancer. Our findings indicate a modification in a range of pathways associated with cell cycle, extracellular matrix, and DNA repair in these three malignancies. Results showed that fibrosarcoma (FS), rhabdomyosarcoma (RMS), and osteosarcoma (OS) had 653, 1270, and 2823 differentially expressed genes (DEGs), respectively. Interestingly, there were 24 DEGs common to all three types. Network analysis showed that the fibrosarcoma network had two sub-networks identified in FS that contributed to the catabolic process of collagen via the G-protein coupled receptor signaling pathway. The rhabdomyosarcoma network included nine sub-networks associated with cell division, extracellular matrix organization, mRNA splicing via spliceosome, and others. The osteosarcoma network has 13 sub-networks, including mRNA splicing, sister chromatid cohesion, DNA repair, etc. In conclusion, the common DEGs identified in this study have been shown to play significant and multiple roles in various other cancers based on the literature review, indicating their significance.
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Affiliation(s)
- Mehran Radak
- Department of Biology, School of Sciences, Razi University, Baq-e-Abrisham, Kermanshah, 6714967346, Iran.
| | - Nakisa Ghamari
- Department of Biology, School of Sciences, Razi University, Baq-e-Abrisham, Kermanshah, 6714967346, Iran.
| | - Hossein Fallahi
- Department of Biology, School of Sciences, Razi University, Baq-e-Abrisham, Kermanshah, 6714967346, Iran.
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Janssens K, Neefs I, Ibrahim J, Schepers A, Pauwels P, Peeters M, Van Camp G, Op de Beeck K. Epigenome-wide methylation analysis of colorectal carcinoma, adenoma and normal tissue reveals novel biomarkers addressing unmet clinical needs. Clin Epigenetics 2023; 15:111. [PMID: 37415235 PMCID: PMC10327366 DOI: 10.1186/s13148-023-01516-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 06/01/2023] [Indexed: 07/08/2023] Open
Abstract
BACKGROUND Biomarker discovery in colorectal cancer has mostly focused on methylation patterns in normal and colorectal tumor tissue, but adenomas remain understudied. Therefore, we performed the first epigenome-wide study to profile methylation of all three tissue types combined and to identify discriminatory biomarkers. RESULTS Public methylation array data (Illumina EPIC and 450K) were collected from a total of 1 892 colorectal samples. Pairwise differential methylation analyses between tissue types were performed for both array types to "double evidence" differentially methylated probes (DE DMPs). Subsequently, the identified DMPs were filtered on methylation level and used to build a binary logistic regression prediction model. Focusing on the clinically most interesting group (adenoma vs carcinoma), we identified 13 DE DMPs that could effectively discriminate between them (AUC = 0.996). We validated this model in an in-house experimental methylation dataset of 13 adenomas and 9 carcinomas. It reached a sensitivity and specificity of 96% and 95%, respectively, with an overall accuracy of 96%. Our findings raise the possibility that the 13 DE DMPs identified in this study can be used as molecular biomarkers in the clinic. CONCLUSIONS Our analyses show that methylation biomarkers have the potential to discriminate between normal, precursor and carcinoma tissues of the colorectum. More importantly, we highlight the power of the methylome as a source of markers for discriminating between colorectal adenomas and carcinomas, which currently remains an unmet clinical need.
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Affiliation(s)
- Katleen Janssens
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Isabelle Neefs
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Joe Ibrahim
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Anne Schepers
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
| | - Patrick Pauwels
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Marc Peeters
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Guy Van Camp
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium
| | - Ken Op de Beeck
- Centre of Medical Genetics, University of Antwerp and Antwerp University Hospital, Prins Boudewijnlaan 43, 2650, Edegem, Belgium.
- Centre for Oncological Research Antwerp (CORE), University of Antwerp and Antwerp University Hospital, Universiteitsplein 1, 2610, Wilrijk, Belgium.
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10
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Lu C, Zhang X, Schardey J, Wirth U, Heinrich K, Massiminio L, Cavestro GM, Neumann J, Bazhin AV, Werner J, Kühn F. Molecular characteristics of microsatellite stable early-onset colorectal cancer as predictors of prognosis and immunotherapeutic response. NPJ Precis Oncol 2023; 7:63. [PMID: 37393364 DOI: 10.1038/s41698-023-00414-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Accepted: 06/15/2023] [Indexed: 07/03/2023] Open
Abstract
The incidence of early-onset colorectal cancer (EO-CRC, in patients younger than 50) is increasing worldwide. The specific gene signatures in EO-CRC patients are largely unknown. Since EO-CRC with microsatellite instability is frequently associated with Lynch syndrome, we aimed to comprehensively characterize the tumor microenvironment (TME) and gene expression profiles of EO-CRC with microsatellite stable (MSS-EO-CRC). Here, we demonstrated that MSS-EO-CRC has a similar pattern of tumor-infiltrating immune cells, immunotherapeutic responses, consensus molecular subtypes, and prognosis as late-onset CRC with MSS (MSS-LO-CRC). 133 differential expressed genes were identified as unique gene signatures of MSS-EO-CRC. Moreover, we established a risk score, which was positively associated with PD-L1 expression and could reflect both the level of tumor-infiltrating immune cells and the prognosis of MSS-EO-CRC patients. Application of this score on the anti-PD-L1 treatment cohort demonstrated that the low-risk score group has significant therapeutic advantages and clinical benefits. In addition, candidate driver genes were identified in the different-sidedness of MSS-EO-CRC patients. Altogether, MSS-EO-CRC exhibits distinct molecular profiles that differ from MSS-LO-CRC even though they have a similar TME characterization and survival pattern. Our risk score appears to be robust enough to predict prognosis and immunotherapeutic response and therefore could help to optimize the treatment of MSS-EO-CRC.
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Affiliation(s)
- Can Lu
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention (Ministry of Education), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
- Zhejiang Provincial Clinical Research Center for CANCER & Cancer Center of Zhejiang University, Hangzhou, China
| | - Xiaopeng Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China
- Institute of Laboratory Medicine, University Hospital of LMU Munich, Munich, Germany
| | - Josefine Schardey
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
| | - Ulrich Wirth
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
| | - Kathrin Heinrich
- Department of Medicine III, University Hospital, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
| | - Luca Massiminio
- Experimental Gastroenterology Laboratory, Gastroenterology and Endoscopy Department, San Raffaele Scientific Institute, Milano, Italy
| | - Giulia Martina Cavestro
- Experimental Gastroenterology Laboratory, Gastroenterology and Endoscopy Department, San Raffaele Scientific Institute, Milano, Italy
| | - Jens Neumann
- Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, 81377, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Partner Site Munich, Munich, Germany
| | - Alexandr V Bazhin
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, 81377, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Partner Site Munich, Munich, Germany
| | - Jens Werner
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany
- German Cancer Consortium (DKTK), Partner Site Munich, 81377, Munich, Germany
- Bavarian Cancer Research Center (BZKF), Partner Site Munich, Munich, Germany
| | - Florian Kühn
- Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, 81377, Munich, Germany.
- German Cancer Consortium (DKTK), Partner Site Munich, 81377, Munich, Germany.
- Bavarian Cancer Research Center (BZKF), Partner Site Munich, Munich, Germany.
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11
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Selvaggi F, Catalano T, Lattanzio R, Cotellese R, Aceto GM. Wingless/It/β-catenin signaling in liver metastasis from colorectal cancer: A focus on biological mechanisms and therapeutic opportunities. World J Gastroenterol 2023; 29:2764-2783. [PMID: 37274070 PMCID: PMC10237106 DOI: 10.3748/wjg.v29.i18.2764] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/28/2023] [Accepted: 04/17/2023] [Indexed: 05/11/2023] Open
Abstract
The liver is the most common site of metastases in patients with colorectal cancer. Colorectal liver metastases (CRLMs) are the result of molecular mechanisms that involve different cells of the liver microenvironment. The aberrant activation of Wingless/It (Wnt)/β-catenin signals downstream of Wnt ligands initially drives the oncogenic transformation of the colon epithelium, but also the progression of metastatization through the epithelial-mesenchymal transition/mesenchymal-epithelial transition interactions. In liver microenvironment, metastatic cells can also survive and adapt through dormancy, which makes them less susceptible to pro-apoptotic signals and therapies. Treatment of CRLMs is challenging due to its variability and heterogeneity. Advances in surgery and oncology have been made in the last decade and a pivotal role for Wnt/β-catenin pathway has been re-cognized in chemoresistance. At the state of art, there is a lack of clear understanding of why and how this occurs and thus where exactly the opportunities for developing anti-CRLMs therapies may lie. In this review, current knowledge on the involvement of Wnt signaling in the development of CRLMs was considered. In addition, an overview of useful biomarkers with a revision of surgical and non-surgical therapies currently accepted in the clinical practice for colorectal liver metastasis patients were provided.
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Affiliation(s)
- Federico Selvaggi
- Department of Surgical, ASL2 Lanciano-Vasto-Chieti, Ospedale Clinicizzato SS Annunziata of Chieti, Chieti 66100, Italy
| | - Teresa Catalano
- Department of Clinical and Experimental Medicine, University of Messina, Messina 98125, Italy
| | - Rossano Lattanzio
- Department of Innovative Technologies in Medicine & Dentistry, University “G. d’Annunzio” Chieti-Pescara, Chieti 66100, Italy
| | - Roberto Cotellese
- Department of Medical, Oral and Biotechnological Sciences, University “G. d’Annunzio” Chieti-Pescara, Chieti 66100, Italy
- Villa Serena Foundation for Research, Villa Serena - Del Dott. L. Petruzzi, Città Sant’Angelo 65013, Pescara, Italy
| | - Gitana Maria Aceto
- Department of Medical, Oral and Biotechnological Sciences, “G. d’Annunzio” University of Chieti-Pescara, Chieti 66100, Italy
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12
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Lin C, Chen Y, Pan J, Lu Q, Ji P, Lin S, Liu C, Lin S, Li M, Zong J. Identification of an individualized therapy prognostic signature for head and neck squamous cell carcinoma. BMC Genomics 2023; 24:221. [PMID: 37106442 PMCID: PMC10142243 DOI: 10.1186/s12864-023-09325-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 04/20/2023] [Indexed: 04/29/2023] Open
Abstract
BACKGROUND Head and neck squamous cell carcinoma (HNSCC) are the most common cancers in the head and neck. Therapeutic response-related genes (TRRGs) are closely associated with carcinogenesis and prognosis in HNSCC. However, the clinical value and prognostic significance of TRRGs are still unclear. We aimed to construct a prognostic risk model to predict therapy response and prognosis in TRRGs-defined subgroups of HNSCC. METHODS The multiomics data and clinical information of HNSCC patients were downloaded from The Cancer Genome Atlas (TCGA). The profile data GSE65858 and GSE67614 chip was downloaded from public functional genomics data Gene Expression Omnibus (GEO). Based on TCGA-HNSC database, patients were divided into a remission group and a non-remission group according to therapy response, and differentially expressed TRRGs between those two groups were screened. Using Cox regression analysis and Least absolute shrinkage and selection operator (LASSO) analysis, candidate TRRGs that can predict the prognosis of HNSCC were identified and used to construct a TRRGs-based signature and a prognostic nomogram. RESULT A total of 1896 differentially expressed TRRGs were screened, including 1530 upregulated genes and 366 downregulated genes. Then, 206 differently expressed TRRGs that was significantly associated with the survival were chosen using univariate Cox regression analysis. Finally, a total of 20 candidate TRRGs genes were identified by LASSO analysis to establish a signature for risk prediction, and the risk score of each patient was calculated. Patients were divided into a high-risk group (Risk-H) and a low-risk group (Risk-L) based on the risk score. Results showed that the Risk-L patients had better overall survival (OS) than Risk-H patients. Receiver operating characteristic (ROC) curve analysis revealed great predictive performance for 1-, 3-, and 5-year OS in TCGA-HNSC and GEO databases. Moreover, for patients treated with post-operative radiotherapy, Risk-L patients had longer OS and lower recurrence than Risk-H patients. The nomogram involves risk score and other clinical factors had good performance in predicting survival probability. CONCLUSIONS The proposed risk prognostic signature and Nomogram based on TRRGs are novel promising tools for predicting therapy response and overall survival in HNSCC patients.
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Affiliation(s)
- Cheng Lin
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian Province, China
| | - Yuebing Chen
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian Province, China
| | - Jianji Pan
- Department of Radiation Oncology, Fujian Medical University Xiamen Humanity Hospital, Xiamen, Fujian Province, China
| | - Qiongjiao Lu
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian Province, China
| | - Pengjie Ji
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian Province, China
| | - Shuiqin Lin
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian Province, China
| | - Chunfeng Liu
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian Province, China
| | - Shaojun Lin
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian Province, China
| | - Meifang Li
- Department of Medical Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350300, Fujian Province, China.
| | - Jingfeng Zong
- Department of Radiation Oncology, Clinical Oncology School of Fujian Medical University, Fujian Cancer Hospital, Fuzhou, 350014, Fujian Province, China.
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13
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Voutsadakis IA. KRAS mutated colorectal cancers with or without PIK3CA mutations: Clinical and molecular profiles inform current and future therapeutics. Crit Rev Oncol Hematol 2023; 186:103987. [PMID: 37059275 DOI: 10.1016/j.critrevonc.2023.103987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 03/13/2023] [Accepted: 04/11/2023] [Indexed: 04/16/2023] Open
Abstract
BACKGROUND Colorectal cancer is one of the most prevalent malignancies and its molecular pathogenesis has been intensely investigated for several decades. As a result, great progress has been made and targeted therapies have been introduced in the clinic. This paper examines colorectal cancers based on two of the most common molecular alterations, KRAS and PIK3CA mutations as a basis for therapeutic targeting. METHODS Two publicly available genomic series with clinical data were evaluated for prevalence and characteristics of cases with and without KRAS and PIK3CA mutations and the literature was reviewed for relevant information on the therapeutic implication of these alterations as well as other coincident alterations to derive therapeutic individualized options of targeted treatments. RESULTS Colorectal cancers without KRAS and PIK3CA mutations represent the most prevalent group (48% to 58% of patients) and present therapeutic targeted opportunities with BRAF inhibitors and immune checkpoint inhibitors in the subsets with BRAF mutations (15% to 22%) and Microsatellite Instability (MSI, 14% to 16%), respectively. The second most prevalent sub-set, with KRAS mutations and PIK3CA wild type, representing 20% to 25% of patients, has currently few targeted options, besides specific KRAS G12C inhibitors for the small percentage of cases (9%-10%) that bear this mutation. Cancers with KRAS wild type and PIK3CA mutations are observed in 12% to 14% of colorectal cancer patients, harbor the highest percentage of cases with BRAF mutations and Microsatellite Instability (MSI), and are candidates for the respective targeted therapies. New targeted therapies in development, such as ATR inhibitors could be effective in cases with ATM mutations and ARID1A mutations that are also most prevalent in this sub-group (14% to 22% and 30%, respectively). KRAS and PIK3CA double mutant cancers have also few targeted options currently and could benefit from combination therapies with PI3K inhibitors and new KRAS inhibitors in development. CONCLUSION The backbone of common KRAS and PIK3CA mutations is a rational frame for development of therapeutic algorithms in colorectal cancer and can help guide new drug therapies development. In addition, the prevalence of different molecular groups presented here may help with planning of combination clinical trials by providing estimations of sub-sets with more than one alteration.
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Affiliation(s)
- Ioannis A Voutsadakis
- Algoma District Cancer Program, Sault Area Hospital, Sault Ste. Marie, Ontario, Canada, and Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, Ontario, Canada.
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Meta-Analysis of the Prognostic and Predictive Role of the CpG Island Methylator Phenotype in Colorectal Cancer. DISEASE MARKERS 2022; 2022:4254862. [PMID: 36157209 PMCID: PMC9499813 DOI: 10.1155/2022/4254862] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 08/30/2022] [Indexed: 12/24/2022]
Abstract
Background Various studies have produced contradictory results on the prognostic role of the CpG island methylator phenotype (CIMP) among colorectal cancer (CRC) patients. Although a meta-analysis published in 2014 reported a worse prognosis of CIMP among CIMP-high (CIMP-H) CRC patients, the sample sizes of the major included studies were small. In this study, we included the most recent studies with large sample sizes and performed an updated meta-analysis on the relationship between CIMP and CRC prognosis. Methods A search of MEDLINE, Web of Science, and Cochrane for studies related to CIMP and CRC published until July 2021 was conducted based on the PICO (participant, intervention, control, outcome) framework. Data extraction and literature analyses were performed according to PRISMA standards. Results In the present update, 36 eligible studies (20 recently published) reported survival data in 15315 CRC patients, 18.3% of whom were characterized as CIMP-H. Pooled analysis suggested that CIMP-H was associated with poorer overall survival (OS) (hazard ratio [HR] = 1.37, 95% CI: 1.26–1.48) and disease-free survival/progression-free survival/recurrence-free survival (DFS/PFS/RFS) (HR = 1.51, 95% CI: 1.19–1.91) among CRC patients. Subgroup analysis based on tumor stage and DNA mismatch repair (MMR) status showed that only patients with stages III-IV and proficient MMR (pMMR) tumors showed a significant association between CIMP-H and shorter OS, with HRs of 1.52 and 1.37, respectively. Three studies were pooled to explore the predictive value of CIMP on CRC patient DFS after receiving postoperative chemotherapy, and no significant correlation was found. Conclusion CIMP-H is associated with a significantly poor prognosis in CRC patients, especially those with stage III-IV and pMMR tumors. However, the predictive value of CIMP needs to be confirmed by more prospective randomized studies.
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Ciombor KK, Strickler JH, Bekaii-Saab TS, Yaeger R. BRAF-Mutated Advanced Colorectal Cancer: A Rapidly Changing Therapeutic Landscape. J Clin Oncol 2022; 40:2706-2715. [PMID: 35649231 PMCID: PMC9390817 DOI: 10.1200/jco.21.02541] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 01/07/2022] [Accepted: 03/07/2022] [Indexed: 12/13/2022] Open
Abstract
BRAF-mutated advanced colorectal cancer is a relatively small but critical subset of this tumor type on the basis of prognostic and predictive implications. BRAF alterations in colorectal cancer are classified into three functional categories on the basis of signaling mechanisms, with the class I BRAFV600E mutation occurring most frequently in colorectal cancer. Functional categorization of BRAF mutations in colorectal cancer demonstrates distinct mitogen-activated protein kinase pathway signaling. On the basis of recent clinical trials, current standard-of-care therapies for patients with BRAFV600E-mutated metastatic colorectal cancer include first-line cytotoxic chemotherapy plus bevacizumab and subsequent therapy with the BRAF inhibitor encorafenib and antiepidermal growth factor receptor antibody cetuximab. Treatment regimens currently under exploration in BRAFV600E-mutant metastatic colorectal cancer include combinatorial options of various pathway-targeted therapies, cytotoxic chemotherapy, and/or immune checkpoint blockade, among others. Circumvention of adaptive and acquired resistance to BRAF-targeted therapies is a significant challenge to be overcome in BRAF-mutated advanced colorectal cancer.
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Affiliation(s)
- Kristen K. Ciombor
- Division of Hematology/Oncology, Department of Internal Medicine, Vanderbilt University Medical Center, Nashville, TN
| | - John H. Strickler
- Division of Medical Oncology, Department of Internal Medicine, Duke University Medical Center, Durham, NC
| | | | - Rona Yaeger
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
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Effect of DNA methylation status on first-line anti-epidermal growth factor receptor treatment in patients with metastatic colorectal cancer. Int J Colorectal Dis 2022; 37:1439-1447. [PMID: 35612620 DOI: 10.1007/s00384-022-04177-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/01/2022] [Indexed: 02/04/2023]
Abstract
PURPOSE The CpG island methylator phenotype (CIMP), important for carcinogenesis, is a predictor of prognosis and chemotherapy sensitivity in colorectal cancer (CRC). However, there is a lack of consensus on CIMP markers, and thus, more comprehensive methylation markers are required to reliably predict the clinical outcomes. This study aimed to clarify the effects of genome-wide DNA methylation status on clinical outcomes in patients with metastatic CRC (mCRC) treated with epidermal growth factor receptor (EGFR) inhibitors. METHODS We enrolled 241 patients with mCRC, who received chemotherapy plus EGFR inhibitors as a first-line treatment. We analyzed the incidence and clinicopathological characteristics of highly methylated CRC (HMCC) and associations between genome-wide DNA methylation status and response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS In total, 169 patients were included in the final analyses. The frequency of HMCC was 8.9% (15/169). The characteristics of patients with HMCC included right-sided primary tumor location (P = 0.042), undifferentiated histology (P = 0.047), and BRAF V600E mutation (P < 0.0001). Patients with HMCC showed worse clinical outcomes than those with low-methylated CRC in terms of RR (P = 0.017), PFS (P = 0.004), and OS (P = 0.019). In the multivariate analysis, peritoneal metastasis (P = 0.017), methylation status (P = 0.037), and BRAF V600E mutations (P = 0.0001) were independent factors for shorter PFS. CONCLUSIONS Genome-wide DNA methylation status is an independent factor associated with PFS in patients with mCRC treated with first-line EGFR inhibitors.
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Otsuki Y, Ouchi K, Takahashi S, Sasaki K, Sakamoto Y, Okita A, Ishioka C. Altered gene expression due to aberrant DNA methylation correlates with responsiveness to anti-EGFR antibody treatment. Cancer Sci 2022; 113:3221-3233. [PMID: 35403373 PMCID: PMC9459254 DOI: 10.1111/cas.15367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 03/26/2022] [Accepted: 04/03/2022] [Indexed: 11/29/2022] Open
Abstract
The cetuximab gene expression signature and DNA methylation status of colorectal cancer (CRC) are predictive of the therapeutic effects of anti‐epidermal growth factor receptor (EGFR) antibody therapy. As DNA methylation is a means of regulating gene expression, it may play an important role in the expression of cetuximab signature genes. This study aims to determine the effects of aberrant DNA methylation on the regulation of cetuximab signature gene expression. Comprehensive DNA methylation and gene expression data were retrieved from CRC patients in three tumor tissue (TT) cohorts and three normal colorectal mucosa/tumor tissue paired (NCM‐TT) cohorts. Of the 231 cetuximab signature genes, 57 exhibited an inverse correlation between the methylation of promoter CpG sites and gene expression level in multiple cohorts. About two‐thirds of the promoter CpG sites associated with the 57 genes exhibited this correlation. In all 57 gene promoter regions, the methylation levels in NCMs did not differ according to comparisons based on cetuximab signature or DNA methylation status classification of matched TTs. Thus, the altered expression of 57 genes was caused by aberrant DNA methylation during carcinogenesis. Analysis of the association between cetuximab signature or DNA methylation status and progression‐free survival (PFS) of anti‐EGFR antibody agents in the same cohort showed that DNA methylation status was most associated with PFS. In conclusion, we found that aberrant DNA methylation regulates specific gene expression in cetuximab signature during carcinogenesis, suggesting that it is one of the important determinants of sensitivity to anti‐EGFR antibody agents.
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Affiliation(s)
- Yasufumi Otsuki
- Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.,Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan
| | - Kota Ouchi
- Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.,Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan
| | - Shin Takahashi
- Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.,Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan
| | - Keiju Sasaki
- Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.,Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan
| | - Yasuhiro Sakamoto
- Department of Medical Oncology, Osaki Citizen Hospital, Miyagi, Japan
| | - Akira Okita
- Department of Medical Oncology, Osaki Citizen Hospital, Miyagi, Japan
| | - Chikashi Ishioka
- Department of Clinical Oncology, Institute of Development, Aging and Cancer, Tohoku University, Miyagi, Japan.,Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan.,Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Miyagi, Japan
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18
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Ouchi K, Takahashi S, Okita A, Sakamoto Y, Muto O, Amagai K, Okada T, Ohori H, Shinozaki E, Ishioka C. A modified MethyLight assay predicts the clinical outcomes of anti-EGFR treatment in metastatic colorectal cancer. Cancer Sci 2021; 113:1057-1068. [PMID: 34962023 PMCID: PMC8898715 DOI: 10.1111/cas.15252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2021] [Accepted: 11/22/2021] [Indexed: 12/24/2022] Open
Abstract
DNA methylation status correlates with clinical outcomes of anti‐epidermal growth factor receptor (EGFR) treatment. There is a strong need to develop a simple assay for measuring DNA methylation status for the clinical application of drug selection based on it. In this study, we collected data from 186 patients with metastatic colorectal cancer (mCRC) who had previously received anti‐EGFR treatment. We modified MethyLite to develop a novel assay to classify patients as having highly methylated colorectal cancer (HMCC) or low‐methylated colorectal cancer (LMCC) based on the methylation status of 16 CpG sites of tumor‐derived genomic DNA in the development cohort (n = 30). Clinical outcomes were then compared between the HMCC and LMCC groups in the validation cohort (n = 156). The results showed that HMCC had a significantly worse response rate (4.2% vs 33.3%; P = .004), progression‐free survival (median: 2.5 vs 6.6 mo, P < .001, hazard ratio [HR] = 0.22), and overall survival (median: 5.6 vs 15.5 mo, P < .001, HR = 0.23) than did LMCC in patients with RAS wild‐type mCRC who were refractory or intolerable to oxaliplatin‐ and irinotecan‐based chemotherapy (n = 101). The DNA methylation status was an independent predictive factor and a more accurate biomarker than was the primary site of anti‐EGFR treatment. In conclusion, our novel DNA methylation measurement assay based on MethyLight was simple and useful, suggesting its implementation as a complementary diagnostic tool in a clinical setting.
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Affiliation(s)
- Kota Ouchi
- Department of Clinical Oncology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Miyagi, Japan.,Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan
| | - Shin Takahashi
- Department of Clinical Oncology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Miyagi, Japan.,Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan
| | - Akira Okita
- Department of Clinical Oncology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Miyagi, Japan.,Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan
| | - Yasuhiro Sakamoto
- Department of Medical Oncology, Osaki Citizen Hospital, Miyagi, Japan
| | - Osamu Muto
- Department of Medical Oncology, Akita Red Cross Hospital, Akita, Japan
| | - Kenji Amagai
- Department of Gastroenterology, Ibaraki Prefectural Central Hospital, Ibaraki Cancer Center, Ibaraki, Japan
| | - Takaho Okada
- Department of Digestive Surgery, Sendai Open Hospital, Miyagi, Japan
| | - Hisatsugu Ohori
- Department of Medical Oncology, Ishinomaki Red Cross Hospital, Miyagi, Japan
| | - Eiji Shinozaki
- Gastrointestinal Oncology Department, The Cancer Institute Hospital of JFCR, Tokyo, Japan
| | - Chikashi Ishioka
- Department of Clinical Oncology, Institute of Development, Aging and Cancer (IDAC), Tohoku University, Miyagi, Japan.,Department of Medical Oncology, Tohoku University Hospital, Miyagi, Japan.,Department of Clinical Oncology, Tohoku University Graduate School of Medicine, Miyagi, Japan
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19
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Cheng WL, Feng PH, Lee KY, Chen KY, Sun WL, Van Hiep N, Luo CS, Wu SM. The Role of EREG/EGFR Pathway in Tumor Progression. Int J Mol Sci 2021; 22:ijms222312828. [PMID: 34884633 PMCID: PMC8657471 DOI: 10.3390/ijms222312828] [Citation(s) in RCA: 102] [Impact Index Per Article: 25.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 11/22/2021] [Accepted: 11/23/2021] [Indexed: 12/12/2022] Open
Abstract
Aberrant activation of the epidermal growth factor receptor (EGFR/ERBB1) by erythroblastic leukemia viral oncogene homolog (ERBB) ligands contributes to various tumor malignancies, including lung cancer and colorectal cancer (CRC). Epiregulin (EREG) is one of the EGFR ligands and is low expressed in most normal tissues. Elevated EREG in various cancers mainly activates EGFR signaling pathways and promotes cancer progression. Notably, a higher EREG expression level in CRC with wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS) is related to better efficacy of therapeutic treatment. By contrast, the resistance of anti-EGFR therapy in CRC was driven by low EREG expression, aberrant genetic mutation and signal pathway alterations. Additionally, EREG overexpression in non-small cell lung cancer (NSCLC) is anticipated to be a therapeutic target for EGFR-tyrosine kinase inhibitor (EGFR-TKI). However, recent findings indicate that EREG derived from macrophages promotes NSCLC cell resistance to EGFR-TKI treatment. The emerging events of EREG-mediated tumor promotion signals are generated by autocrine and paracrine loops that arise from tumor epithelial cells, fibroblasts, and macrophages in the tumor microenvironment (TME). The TME is a crucial element for the development of various cancer types and drug resistance. The regulation of EREG/EGFR pathways depends on distinct oncogenic driver mutations and cell contexts that allows specific pharmacological targeting alone or combinational treatment for tailored therapy. Novel strategies targeting EREG/EGFR, tumor-associated macrophages, and alternative activation oncoproteins are under development or undergoing clinical trials. In this review, we summarize the clinical outcomes of EREG expression and the interaction of this ligand in the TME. The EREG/EGFR pathway may be a potential target and may be combined with other driver mutation targets to combat specific cancers.
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Affiliation(s)
- Wan-Li Cheng
- Division of Cardiovascular Surgery, Department of Surgery, Wan Fang Hospital, Taipei Medical University, Taipei 11696, Taiwan;
- Division of Cardiovascular Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Po-Hao Feng
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Kang-Yun Lee
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Kuan-Yuan Chen
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Wei-Lun Sun
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Nguyen Van Hiep
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- International PhD Program in Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
| | - Ching-Shan Luo
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
| | - Sheng-Ming Wu
- Division of Pulmonary Medicine, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, New Taipei City 23561, Taiwan; (P.-H.F.); (K.-Y.L.); (K.-Y.C.); (W.-L.S.); (N.V.H.); (C.-S.L.)
- Division of Pulmonary Medicine, Department of Internal Medicine, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan
- Correspondence:
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20
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Kumbrink J, Li P, Pók-Udvari A, Klauschen F, Kirchner T, Jung A. p130Cas Is Correlated with EREG Expression and a Prognostic Factor Depending on Colorectal Cancer Stage and Localization Reducing FOLFIRI Efficacy. Int J Mol Sci 2021; 22:ijms222212364. [PMID: 34830244 PMCID: PMC8625396 DOI: 10.3390/ijms222212364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 10/31/2021] [Accepted: 11/10/2021] [Indexed: 11/30/2022] Open
Abstract
p130 Crk-associated substrate (p130Cas) is associated with poor prognosis and treatment resistance in breast and lung cancers. To elucidate p130Cas functional and clinical role in colorectal cancer (CRC) progression/therapy resistance, we performed cell culture experiments and bioinformatic/statistical analyses of clinical data sets. p130Cas expression was associated with poor survival in the cancer genome atlas (TCGA) data set. Knockdown/reconstitution experiments showed that p130Cas drives migration but, unexpectedly, inhibits proliferation in CRC cells. TCGA data analyses identified the growth factor epiregulin (EREG) as inversely correlated with p130Cas. p130Cas knockdown and simultaneous EREG treatment further enhanced proliferation. RNA interference and EREG treatment experiments suggested that p130Cas/EREG limit each other’s expression/activity. Inverse p130Cas/EREG Spearman correlations were prominent in right-sided and earlier stage CRC. p130Cas was inducible by 5-fluorouracil (5-FU) and FOLFIRI (folinic acid, 5-FU, irinotecan), and p130Cas and EREG were upregulated in distant metastases (GSE121418). Positive p130Cas/EREG correlations were observed in metastases, preferentially in post-treatment samples (especially pulmonary metastases). p130Cas knockdown sensitized CRC cells to FOLFIRI independent of EREG treatment. RNA sequencing and gene ontology analyses revealed that p130Cas is involved in cytochrome P450 drug metabolism and epithelial-mesenchymal transition. p130Cas expression was associated with poor survival in right-sided, stage I/II, MSS (microsatellite stable), or BRAF-mutated CRC. In summary, p130Cas represents a prognostic factor and potential therapeutic target in CRC.
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Affiliation(s)
- Jörg Kumbrink
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
- German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany
- Correspondence:
| | - Pan Li
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
| | - Agnes Pók-Udvari
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
| | - Frederick Klauschen
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
- German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany
| | - Thomas Kirchner
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
- German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany
| | - Andreas Jung
- Faculty of Medicine, Institute of Pathology, Ludwig-Maximilians-University of Munich, 80337 Munich, Germany; (P.L.); (A.P.-U.); (F.K.); (T.K.); (A.J.)
- German Cancer Consortium (DKTK), Partner Site Munich, 80336 Munich, Germany
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21
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Xu Z, Peng X, Kong Y, Cui Y, Li Y, Guo Y. The best strategy for metastatic colorectal cancer (mCRC) patients in second-line treatment: A network meta-analysis. Cancer Treat Res Commun 2021; 29:100455. [PMID: 34619647 DOI: 10.1016/j.ctarc.2021.100455] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 09/07/2021] [Indexed: 12/24/2022]
Abstract
BACKGROUND Varieties of systemic treatments in second-line treatment for metastatic colorectal cancer (mCRC) patients have showed an improvement on survival. In this study, we performed a systematic review with a pairwise and bayesian network meta-analysis to rank the best strategy for mCRC patients in second-line treatment. METHODS A systematic literature search through 2007 was performed to evaluate the association between several treatment combinations and overall survival (OS), progression-free survival (PFS) and disease control rate (DCR) in mCRC patients. Data were carried out and pooled into a statistical indirect comparison with Bayesian network meta-analysis (NMA). RESULTS 10 trials totally comprised 4183 patients were included in our study. In NMA, For PFS, Doublet+Bev showed benefits in comparing with Doublet, Doulblet+placebo and Doublet+Ramucirumab. Also, Doublet+Aflibercept demonstrated its superiority in comparing with Doulblet+placebo. For OS, Doublet+Bev represented its superiority when comparing with Double and Doublet+placebo. Doublet+Aflibercept and Doublet+Ramucirumab also done well when opposed to Doublet+placebo. For DCR, Doublet+bev showed unique superiority when compared with Doublet, And Doublet+targeted agent did not represent benefits to each other in DCR. Doublet+bev ranked highest in terms of PFS, OS and DCR followed by Doublet+panitumumab, Doublet+placebo was the lowest in terms of PFS and OS. CONCLUSIONS Our study shows that Doublet+Bev has the major probability to provide an improvement of survival in patients with mCRC.
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Affiliation(s)
- Zhili Xu
- First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang 310053, China
| | - Xinyi Peng
- First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang 310053, China
| | - Yanni Kong
- First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang 310053, China
| | - Yiyi Cui
- First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang 310053, China; The Third Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, 310000, China
| | - Yan Li
- The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, 310006, China.
| | - Yong Guo
- First Clinical Medical College, Zhejiang Chinese Medical University, Zhejiang 310053, China; The First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang, 310006, China.
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22
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Liu Y, Baggerly KA, Orouji E, Manyam G, Chen H, Lam M, Davis JS, Lee MS, Broom BM, Menter DG, Rai K, Kopetz S, Morris JS. Methylation-eQTL Analysis in Cancer Research. Bioinformatics 2021; 37:4014-4022. [PMID: 34117863 PMCID: PMC9188481 DOI: 10.1093/bioinformatics/btab443] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Revised: 03/15/2021] [Accepted: 06/11/2021] [Indexed: 11/13/2022] Open
Abstract
MOTIVATION DNA methylation is a key epigenetic factor regulating gene expression. While promoter methylation has been well studied, recent publications have revealed that functionally important methylation also occurs in intergenic and distal regions, and varies across genes and tissue types. Given the growing importance of inter-platform integrative genomic analyses, there is an urgent need to develop methods to discover and characterize gene-level relationships between methylation and expression. RESULTS We introduce a novel sequential penalized regression approach to identify methylation-expression quantitative trait loci (methyl-eQTLs), a term that we have coined to represent, for each gene and tissue type, a sparse set of CpG loci best explaining gene expression and accompanying weights indicating direction and strength of association. Using TCGA and MD Anderson colorectal cohorts to build and validate our models, we demonstrate our strategy better explains expression variability than current commonly used gene-level methylation summaries. The methyl-eQTLs identified by our approach can be used to construct gene-level methylation summaries that are maximally correlated with gene expression for use in integrative models, and produce a tissue-specific summary of which genes appear to be strongly regulated by methylation. Our results introduce an important resource to the biomedical community for integrative genomics analyses involving DNA methylation. AVAILABILITY AND IMPLEMENTATION We produce an R Shiny app (https://rstudio-prd-c1.pmacs.upenn.edu/methyl-eQTL/) that interactively presents methyl-eQTL results for colorectal, breast, and pancreatic cancer. The source R code for this work is provided in the supplement. SUPPLEMENTARY INFORMATION Supplementary data are available at Bioinformatics online.
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Affiliation(s)
- Yusha Liu
- Department of Human Genetics, The University of Chicago, Chicago, IL 60637, USA
| | - Keith A Baggerly
- Department of Bioinformatics and Computational Biology, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Elias Orouji
- Department of Genomic Medicine, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Ganiraju Manyam
- Department of Bioinformatics and Computational Biology, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Huiqin Chen
- Department of Bioinformatics and Computational Biology, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael Lam
- Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Jennifer S Davis
- Department of Epidemiology, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael S Lee
- Department of Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Bradley M Broom
- Department of Bioinformatics and Computational Biology, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - David G Menter
- Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Kunal Rai
- Department of Genomic Medicine, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, M.D. Anderson Cancer Center, Houston, TX 77030, USA
| | - Jeffrey S Morris
- Department of Biostatistics, Epidemiology and Informatics, The University of Pennsylvania, Philadelphia, PA 19104-6021, USA
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23
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Advani SM, Swartz MD, Loree J, Davis JS, Sarsashek AM, Lam M, Lee MS, Bressler J, Lopez DS, Daniel CR, Morris V, Shureqi I, Kee B, Dasari A, Vilar E, Overman M, Hamilton S, Maru D, Braithwaite D, Kopetz S. Epidemiology and Molecular-Pathologic Characteristics of CpG Island Methylator Phenotype (CIMP) in Colorectal Cancer. Clin Colorectal Cancer 2021; 20:137-147.e1. [PMID: 33229221 DOI: 10.1016/j.clcc.2020.09.007] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/15/2020] [Accepted: 09/18/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND CpG island methylator phenotype (CIMP) forms a distinct epigenetic phenotype in colorectal cancer (CRC). Though associated with distinct clinicopathologic characteristics, limited evidence exists of the association of CIMP with patient's reported lifestyle factors and tumor molecular characteristics. We assessed the associations of these characteristics in a pooled analysis of CRC patients. PATIENTS AND METHODS We pooled data from 3 CRC patient cohorts: Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC), biomarker-based protocol (Integromics), and The Cancer Genome Atlas (TCGA). CIMP was measured using the classical 6-gene methylated-in-tumor (MINT) marker panel (MINT1, MINT2, MINT31, p14, p16, and MLH1) in ATTACC and genome-wide human methylation arrays in Integromics and TCGA, respectively. CIMP-High (CIMP-H) was defined as ≥ 3 of 6 methylated markers in ATTACC. In TCGA and Integromics, CIMP-H group was defined on the basis of clusters of methylation profiles and high levels of methylation in tumor samples. Baseline comparisons of characteristics across CIMP groups (CIMP-H vs. CIMP-0) were performed by Student t test or chi-square test for continuous or categorical variables, respectively. Further logistic regression analyses were performed to compute the odds ratio (OR) of these associations. RESULTS Pooled prevalence of CIMP-H was 22% across 3 data sets. CIMP-H CRC tumors were associated with older age at diagnosis (OR, 1.02; 95% confidence interval [CI], 1.01, 1.03), microsatellite instability-high (MSI-H) status (OR, 9.15; 95% CI, 4.45, 18.81), BRAF mutation (OR, 7.70; 95% CI, 4.98, 11.87), right-sided tumor location (OR, 2.40; 95% CI, 1.78, 3.22), poor differentiation (OR, 2.94; 95% CI, 1.95, 4.45), and mucinous histology (OR, 2.47; 95% CI, 1.77, 3.47), as reported previously in the literature. CIMP-H tumors were also found to be associated with self-reported history of alcohol consumption (OR, ever vs. never, 1.58; 95% CI, 1.07, 2.34). Pathologically, CIMP-H tumors were associated with the presence of intraepithelial lymphocytes (OR, 3.31; 95% CI, 1.41, 7.80) among patients in the Integromics cohort. CONCLUSION CIMP-H tumors were associated with history of alcohol consumption and presence of intraepithelial lymphocytes. In addition, we confirmed the previously known association of CIMP with age, MSI-H status, BRAF mutation, sidedness, and mucinous histology. Molecular pathologic epidemiology associations help us explore the underlying association of lifestyle and clinical factors with molecular subsets like CIMP and help guide cancer prevention and treatment strategies.
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Affiliation(s)
- Shailesh M Advani
- Social Behavioral Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, MD; Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Oncology, Georgetown University School of Medicine, Washington, DC.
| | - Michael D Swartz
- Department of Biostatistics and Data Science, University of Texas Health Science Center at Houston, Houston, TX
| | - Jonathan Loree
- Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jennifer S Davis
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Amir Mehvarz Sarsashek
- Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael Lam
- Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael Sangmin Lee
- Division of Gastrointestinal Oncology, University of North Carolina Chapel Hill, Chapel Hill, NC
| | - Jan Bressler
- Department of Epidemiology, Human Genetics and Environmental Sciences, University of Texas Health Science Center at Houston, School of Public Health, Houston, TX
| | - David S Lopez
- Department of Preventive Medicine and Population Health, UTMB School of Medicine, Galveston, TX
| | - Carrie R Daniel
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Van Morris
- Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Imad Shureqi
- Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Bryan Kee
- Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Arvind Dasari
- Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael Overman
- Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Stanley Hamilton
- Division of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dipen Maru
- Division of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dejana Braithwaite
- Department of Oncology, Georgetown University School of Medicine, Washington, DC
| | - Scott Kopetz
- Division of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
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24
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Wensink E, Bond M, Kucukkose E, May A, Vink G, Koopman M, Kranenburg O, Roodhart J. A review of the sensitivity of metastatic colorectal cancer patients with deficient mismatch repair to standard-of-care chemotherapy and monoclonal antibodies, with recommendations for future research. Cancer Treat Rev 2021; 95:102174. [PMID: 33721596 DOI: 10.1016/j.ctrv.2021.102174] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 02/17/2021] [Accepted: 02/19/2021] [Indexed: 12/29/2022]
Abstract
In 5% of metastatic colorectal cancer (mCRC) patients, tumours display a deficient mismatch repair (dMMR) system. Immunotherapy is beneficial in dMMR mCRC patients and has recently been approved by the Food and Drug Administration for patients with unresectable or metastatic dMMR CRC. Although dMMR and proficient MMR (pMMR) CRC tumours are biologically distinct, they are commonly treated with the same chemotherapy and monoclonal antibodies. This includes dMMR mCRC patients who did not respond to immunotherapy (20-30%). However, it is unclear if these treatments are equally beneficial in dMMR mCRC. Of note, dMMR mCRC patients have a worse prognosis compared to pMMR, which may in part be caused by a lower response to treatment. To avoid unnecessary exposure to ineffective treatments and their associated toxicity, it is important to identify which systemic treatments are most beneficial in dMMR mCRC patients, thus improving their outcome. Indeed, future treatment strategies are likely to involve combinations of immunotherapy, chemotherapy and monoclonal antibodies. In this evidence-based review, we summarize clinical trials reporting treatment efficacy of different types of chemotherapy and monoclonal antibodies in dMMR mCRC patients. We also review the biological rationale behind a potential differential benefit of chemotherapy with or without monoclonal antibodies in dMMR mCRC patients. A barrier in the interpretation of preclinical results is the choice of model systems. They largely comprise traditional models, including cell lines and xenografts, rather than more representative models, such as patient-derived organoids. We provide concrete recommendations for clinical investigators and fundamental researchers to accelerate research regarding which systemic therapy is most effective in dMMR mCRC patients.
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Affiliation(s)
- Emerens Wensink
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Marinde Bond
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584CX Utrecht, the Netherlands
| | - Emre Kucukkose
- Department of Surgical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Anne May
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht University, Universiteitsweg 100, 3584CX Utrecht, the Netherlands
| | - Geraldine Vink
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Department of Research and Development, Netherlands Comprehensive Cancer Organisation, Godebaldkwartier 419, 3511DT Utrecht, the Netherlands
| | - Miriam Koopman
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Onno Kranenburg
- Department of Surgical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands; Utrecht Platform for Organoid Technology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands
| | - Jeanine Roodhart
- Department of Medical Oncology, University Medical Center Utrecht, Utrecht University, Heidelberglaan 100, 3584CX Utrecht, the Netherlands.
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25
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Alghamdi MA, AL-Eitan LN, Tarkhan AH, Al-Qarqaz FA. Global gene methylation profiling of common warts caused by human papillomaviruses infection. Saudi J Biol Sci 2021; 28:612-622. [PMID: 33424347 PMCID: PMC7783806 DOI: 10.1016/j.sjbs.2020.10.050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/23/2022] Open
Abstract
Infection with the human papillomaviruses (HPV) often involves the epigenetic modification of the host genome. Despite its prevalence among the population, host genome methylation in HPV-induced warts is not clearly understood. In this study, genome-wide methylation profiling was carried out on paired healthy skin and wart samples in order to investigate the effects that benign HPV infection has on gene methylation status. To overcome this gap in knowledge, paired wart (n = 12) and normal skin (n = 12) samples were obtained from Arab males in order to perform DNA extraction and subsequent genome-wide methylation profiling on the Infinium Methylation EPIC Bead Chip microarray. Analysis of differential methylation revealed a clear pattern of discrimination between the wart and normal skin samples. In warts, the most differentially methylated (DM) genes included long non-coding RNAs (AC005884, AL049646.2, AC126121.2, AP001790.1, and AC107959.3), microRNAs (MIR374B, MIR596, MIR1255B1, MIR26B, and MIR196A2),snoRNAs (SNORD114-22, SNORD70, and SNORD114-31), pseudogenes (AC069366.1, RNU4ATAC11P, AC120057.1, NANOGP3, AC106038.2, TPT1P2, SDC4P, PKMP3, and VN2R3P), and protein-coding genes (AREG, GJB2, C12orf71, AC020909.2, S100A8, ZBED2, FABP7, and CYSLTR1). In addition, pathway analysis revealed that, among the most differentially methylated genes, STAT5A, RARA, MEF2D, MAP3K8, and THRA were the common regulators. It can be observed that HPV-induced warts involve a clear and unique epigenetic alteration to the host genome.
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Affiliation(s)
- Mansour A. Alghamdi
- Department of Anatomy, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia
- Genomics and Personalized Medicine Unit, College of Medicine, King Khalid University, Abha 61421, Saudi Arabia
| | - Laith N. AL-Eitan
- Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan
- Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Amneh H. Tarkhan
- Department of Applied Biological Sciences, Jordan University of Science and Technology, Irbid 22110, Jordan
| | - Firas A. Al-Qarqaz
- Department of Internal Medicine, Jordan University of Science and Technology, Irbid 22110, Jordan
- Division of Dermatology, Department of Internal Medicine, King Abdullah University Hospital Jordan University of Science and Technology, Irbid 22110, Jordan
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26
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Garajova I, Balsano R, Tommasi C, Dalla Valle R, Pedrazzi G, Ravaioli M, Spallanzani A, Leonardi F, Santini C, Caputo F, Riefolo M, Giuffrida M, Gelsomino F. Synchronous and metachronous colorectal liver metastases: impact of primary tumor location on patterns of recurrence and survival after hepatic resection. ACTA BIO-MEDICA : ATENEI PARMENSIS 2020; 92:e2021061. [PMID: 33682832 PMCID: PMC7975968 DOI: 10.23750/abm.v92i1.11050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Accepted: 11/30/2020] [Indexed: 11/23/2022]
Abstract
Background: Considerable differences in terms of prognosis exist between the right-sided (RCC) and the left-sided colon cancer (LCC). Aim of the work: In this study, we evaluated prognostic implications of primary tumor location (PTL) among patients who underwent curative-intent hepatectomy for synchronous (SM) and metachronous (MM) colorectal liver metastases (CRLM). Methods: The study population included all consecutive patients affected by CRLM scheduled for first liver resection at three Italian oncological centers. Results: A total of 204 patients who underwent CRLM resection were included, 50% with RCC. Synchronous lesions were prevalent (n=133, 65%). Median OS was respectively 40.3 months for SM-RCC, 53.5 months for SM-LCC, 64.5 months for MM-RCC and 81.6 months for MM-LCC. Patients with MM-LCC showed an OS better than patients with SM-RCC (p=0.008) and SM-LCC (p=0.002). PTL had no influence on RFS. RCC group had less recurrences (75% vs 86.5%), though further surgery with curative-intent was possible more in LCC group (29.3% vs 32.5%). Cox proportional hazards model analysis showed that age and the presence of SM vs MM was associated with a significantly higher hazard ratio (HR) for death (HR=1.024; 95%CI=1.005-1.043; p=0.011 and HR=2.010; 95%CI=1.328-3.043; p=0.001, respectively). Conclusions: We confirmed that patients with CRLM and right-sided primary colon cancer experience worse survival after hepatic resection. The timing of metastasis has been revealed as important prognostic factor.
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Affiliation(s)
| | - Rita Balsano
- Medical Oncology Unit, University Hospital of Parma.
| | | | | | | | - Matteo Ravaioli
- 3Department of General Surgery and Transplantation, Sant'Orsola-Malpighi Hospital, University of Bologna.
| | | | | | - Chiara Santini
- Department of Oncology and Hematology, University Hospital of Modena.
| | - Francesco Caputo
- Department of Oncology and Hematology, University Hospital of Modena.
| | - Mattia Riefolo
- 5Pathology Unit, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), Sant'Orsola-Malpighi Hospital, University of Bologna.
| | | | - Fabio Gelsomino
- Department of Oncology and Hematology, University Hospital of Modena.
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27
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Stahler A, Stintzing S, Modest DP, Ricard I, Giessen-Jung C, Kapaun C, Ivanova B, Kaiser F, Fischer von Weikersthal L, Moosmann N, Schalhorn A, Stauch M, Kiani A, Held S, Decker T, Moehler M, Neumann J, Kirchner T, Jung A, Heinemann V. Amphiregulin Expression Is a Predictive Biomarker for EGFR Inhibition in Metastatic Colorectal Cancer: Combined Analysis of Three Randomized Trials. Clin Cancer Res 2020; 26:6559-6567. [PMID: 32943459 DOI: 10.1158/1078-0432.ccr-20-2748] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/18/2020] [Accepted: 09/10/2020] [Indexed: 11/16/2022]
Abstract
PURPOSE Amphiregulin (AREG) and epiregulin (EREG) are ligands of EGFR. Predictive information for anti-EGFR treatment in metastatic colorectal cancer (mCRC) was observed, but data for other agents is limited. EXPERIMENTAL DESIGN Ligand mRNA expression; RAS, BRAF, PIK3CA mutations; and EGFR expression were assessed by qRT-PCR, pyrosequencing, and IHC, respectively, in mCRC tumor tissue of patients participating in the randomized controlled trials FIRE-1, CIOX, and FIRE-3. Normalized mRNA expression was dichotomized using median and third quartile. Overall (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier method including univariate and multivariate Cox regression analyses. Penalized spline regression analysis tested interaction of mRNA expression and outcome. RESULTS Of 688 patients with available material, high AREG expression was detected in 343 (>median) and 172 (>3rd quartile) patients. High AREG expression was associated with significantly higher OS [26.2 vs. 21.5 months, HR = 0.80; 95% confidence interval (CI), 0.68-0.94; P = 0.007], PFS (10.0 vs. 8.1 months, HR = 0.74; 95% CI, 0.63-0.86; P = 0.001), and objective response rate (63.1% vs. 51.6%, P = 0.004) compared to low expression at both threshold values. This effect remained significant in multivariate Cox regression analysis (OS: P = 0.01, PFS: P = 0.002). High AREG mRNA expression interacted significantly with the efficacy of cetuximab compared with bevacizumab (OS: P = 0.02, PFS: P = 0.04) in RAS WT mCRC. CONCLUSIONS High AREG mRNA expression is a favorable prognostic biomarker for mCRC which interacted significantly with efficacy of anti-EGFR treatment.
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Affiliation(s)
- Arndt Stahler
- Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany.
| | - Sebastian Stintzing
- Medical Department, Division of Hematology, Oncology and Tumor Immunology (CCM), Charité Universitaetsmedizin Berlin, Berlin, Germany.,DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
| | - Dominik P Modest
- DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Medical Department, Division of Hematology, Oncology and Tumor Immunology (CVK), Charité Universitaetsmedizin Berlin, Berlin, Germany
| | - Ingrid Ricard
- Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany
| | - Clemens Giessen-Jung
- Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany
| | - Christine Kapaun
- Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Boryana Ivanova
- Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | | | | | - Nicolas Moosmann
- Department for Hematology and Oncology, Klinikum Barmherzige Brüder, Regensburg, Germany
| | - Andreas Schalhorn
- Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany
| | | | - Alexander Kiani
- Department of Medicine IV, Klinikum Bayreuth GmbH, Bayreuth, Germany
| | | | | | - Markus Moehler
- I. Department of Internal Medicine, University Medical Center Mainz, Mainz, Germany
| | - Jens Neumann
- DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Thomas Kirchner
- DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Andreas Jung
- DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany.,Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany
| | - Volker Heinemann
- Department of Internal Medicine III and Comprehensive Cancer Centre Munich, University Hospital Grosshadern, Ludwig-Maximilian-Universitaet Muenchen, Munich, Germany.,DKTK, German Cancer Consortium, German Cancer Research Centre (DKFZ), Heidelberg, Germany
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28
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Zhang X, Zuo J, Wang L, Han J, Feng L, Wang Y, Fan Z. Identification of differentially expressed genes between mucinous adenocarcinoma and other adenocarcinoma of colorectal cancer using bioinformatics analysis. J Int Med Res 2020; 48:300060520949036. [PMID: 32840168 PMCID: PMC7450470 DOI: 10.1177/0300060520949036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
Objective As a unique histological subtype of colorectal cancer (CRC), mucinous
adenocarcinoma (MC) has a poor prognosis and responds poorly to treatment.
Genes and markers related to MC have not been reported. Methods To identify biomarkers involved in development of MC compared with other
common adenocarcinoma (AC) subtypes, four datasets were obtained from the
Gene Expression Omnibus database. Differentially expressed genes (DEGs) were
identified using GEO2R. A protein–protein interaction network was
constructed. Functional annotation for DEGs was performed via DAVID,
Metascape, and BiNGO. Significant modules and hub genes were identified
using Cytoscape, and expression of hub genes and relationships between hub
genes and MC were analyzed. Results The DEGs were mainly enriched in negative regulation of cell proliferation,
bicarbonate transport, response to peptide hormone, cell–cell signaling,
cell proliferation, and positive regulation of the canonical Wnt signaling
pathway. The Venn diagram revealed eight significant hub genes:
CXCL9, IDO1, MET,
SNAI2, and ZEB2 were highly expressed
in MC compared with AC, whereas AREG,
TWIST1, and ZEB1 were expressed at a
low level. AREG and MET might be
significant biomarkers for MC. Conclusion The identified DEGs might help elucidate the pathogenesis of MC, identify
potential targets, and improve treatment for CRC.
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Affiliation(s)
- Xue Zhang
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, P. R. China
| | - Jing Zuo
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, P. R. China
| | - Long Wang
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, P. R. China
| | - Jing Han
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, P. R. China
| | - Li Feng
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, P. R. China
| | - Yudong Wang
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, P. R. China
| | - Zhisong Fan
- Department of Medical Oncology, Hebei Medical University Fourth Affiliated Hospital, Shijiazhuang, Hebei, P. R. China
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29
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Li QH, Wang YZ, Tu J, Liu CW, Yuan YJ, Lin R, He WL, Cai SR, He YL, Ye JN. Anti-EGFR therapy in metastatic colorectal cancer: mechanisms and potential regimens of drug resistance. Gastroenterol Rep (Oxf) 2020; 8:179-191. [PMID: 32665850 PMCID: PMC7333932 DOI: 10.1093/gastro/goaa026] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2019] [Revised: 03/27/2020] [Accepted: 04/09/2020] [Indexed: 12/24/2022] Open
Abstract
Cetuximab and panitumumab, as the highly effective antibodies targeting epidermal growth factor receptor (EGFR), have clinical activity in the patients with metastatic colorectal cancer (mCRC). These agents have good curative efficacy, but drug resistance also exists at the same time. The effects of KRAS, NRAS, and BRAF mutations and HER2 amplification on the treatment of refractory mCRC have been elucidated and the corresponding countermeasures have been put forward. However, the changes in EGFR and its ligands, the mutations or amplifications of PIK3CA, PTEN, TP53, MET, HER3, IRS2, FGFR1, and MAP2K1, the overexpression of insulin growth factor-1, the low expression of Bcl-2-interacting mediator of cell death, mismatch repair-deficient, and epigenetic instability may also lead to drug resistance in mCRC. Although the emergence of drug resistance has genetic or epigenetic heterogeneity, most of these molecular changes relating to it are focused on the key signaling pathways, such as the RAS/RAF/mitogen-activated protein kinase or phosphatidylinositol 3-kinase/Akt/mammalian target of the rapamycin pathway. Accordingly, numerous efforts to target these signaling pathways and develop the novel therapeutic regimens have been carried out. Herein, we have reviewed the underlying mechanisms of the resistance to anti-EGFR therapy and the possible implications in clinical practice.
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Affiliation(s)
- Qing-Hai Li
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Ying-Zhao Wang
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jian Tu
- Department of Musculoskeletal Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Chu-Wei Liu
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yu-Jie Yuan
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Run Lin
- Department of Radiology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Wei-Ling He
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Shi-Rong Cai
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Yu-Long He
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
| | - Jin-Ning Ye
- Department of Gastrointestinal Surgery, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, P. R. China
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30
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Foroughi S, Hutchinson RA, Wong HL, Christie M, Batrouney A, Wong R, Lee M, Tie J, Burgess AW, Gibbs P. Immunohistochemical evaluation of the prognostic and predictive power of epidermal growth factor receptor ligand levels in patients with metastatic colorectal cancer. Growth Factors 2020; 38:127-136. [PMID: 33775193 DOI: 10.1080/08977194.2021.1878166] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
For patients with metastatic colorectal cancer (mCRC), epidermal growth factor receptor (EGFR) inhibitors are limited to patients with RAS wild-type tumours. Not all patients will benefit from treatment and better predictive biomarkers are needed. Here we investigated the prognostic and predictive impact of the EGFR ligands amphiregulin (AREG) and epiregulin (EREG). Expression levels were assessed by immunohistochemistry on 99 KRAS wild-type tumours. AREG and EREG positivity was seen in 49% and 50% of cases, respectively. No difference in expression was observed by primary tumour side. There was no significant difference in OS by AREG or EREG expression. In the subset of patients who received an EGFR inhibitor, EREG positivity was associated with longer OS (median 34.0 vs. 27.0 months, p = 0.033), driven by a difference in patients with a left-sided primary (HR 0.37, p = 0.015). Our study supports further investigation into EREG as a predictive biomarker in mCRC.
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Affiliation(s)
- Siavash Foroughi
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
| | - Ryan A Hutchinson
- Colorectal Oncogenomics Group, The University of Melbourne, Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia
- Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia
- University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Victoria, Australia
| | - Hui-Li Wong
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Michael Christie
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Pathology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Ahida Batrouney
- Department of Pathology, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Rachel Wong
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
- Department of Medical Oncology, Eastern Health, Box Hill, Victoria, Australia
- Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia
| | - Margaret Lee
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
- Department of Medical Oncology, Eastern Health, Box Hill, Victoria, Australia
- Eastern Health Clinical School, Monash University, Box Hill, Victoria, Australia
- Department of Medical Oncology, Western Health, St Albans, Victoria, Australia
| | - Jeanne Tie
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
- Department of Medical Oncology, Western Health, St Albans, Victoria, Australia
| | - Antony Wilks Burgess
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
- Department of Surgery, Royal Melbourne Hospital, Parkville, Victoria, Australia
| | - Peter Gibbs
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Victoria, Australia
- Department of Medical Oncology, Western Health, St Albans, Victoria, Australia
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31
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Lin CY, Hsieh PL, Chou CL, Yang CC, Lee SW, Tian YF, Shiue YL, Li WS. High EREG Expression Is Predictive of Better Outcomes in Rectal Cancer Patients Receiving Neoadjuvant Concurrent Chemoradiotherapy. Oncology 2020; 98:549-557. [PMID: 32408308 DOI: 10.1159/000506991] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2020] [Accepted: 03/02/2020] [Indexed: 11/19/2022]
Abstract
BACKGROUND/AIM A great proportion of patients with rectal cancer initially present with locally advanced disease and can potentially benefit from neoadjuvant concurrent chemoradiotherapy (CCRT) for downstaging before surgery. However, risk and clinical outcome stratification remain a great challenge. We aimed to find the potential biomarker to predict the effect of neoadjuvant CCRT on rectal cancer. METHODS We identified epiregulin (EREG) as the most significant predictive marker for neoadjuvant CCRT response from the published rectal cancer transcriptome data set GSE35452. We collected 172 biopsy specimens from rectal cancer patients who received neoadjuvant CCRT followed by radical proctectomy, performed EREG immunohistochemistry, and analyzed the H-scores. We further examined the correlations between the expression level of EREG and clinicopathological features, tumor regression grade, and survival, including disease-specific survival (DSS), locoregional recurrence-free survival (LRFS), and metastasis-free survival (MeFS). RESULTS High EREG expression was significantly related to early pretreatment (pre-Tx) and posttreatment (post-Tx) tumor status (T1, T2, p = 0.047 and p < 0.001), pre-Tx and post-Tx negative nodal status (N0, p < 0.001 and p = 0.004), less vascular and perineurial invasion (p = 0.015 and p = 0.023), and higher tumor regression grade (p < 0.001). In the survival analysis, high EREG expression was significantly associated with better DSS (p < 0.0001), LRFS (p = 0.0004), and MeFS (p < 0.0001). In the multivariate analysis, high EREG expression remained prognostically significant for better DSS (p = 0.003; hazard ratio: 5.599). CONCLUSION These data suggest that EREG is a potential predictive marker and therapeutic target in rectal cancer patients receiving neoadjuvant CCRT.
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Affiliation(s)
- Cheng-Yi Lin
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chi Mei Medical Center, Tainan, Taiwan
| | - Pei-Ling Hsieh
- Department of Medical Imaging, Chi Mei Medical Center, Tainan, Taiwan
| | - Chia-Lin Chou
- Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan.,Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Ching-Chieh Yang
- Department of Radiation Oncology, Chi Mei Medical Center, Tainan, Taiwan
| | - Sung-Wei Lee
- Department of Radiation Oncology, Chi Mei Medical Center, Liouying, Tainan, Taiwan
| | - Yu-Feng Tian
- Division of Colon and Rectal Surgery, Department of Surgery, Chi Mei Medical Center, Tainan, Taiwan
| | - Yow-Ling Shiue
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Wan-Shan Li
- Institute of Biomedical Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan, .,Department of Pathology, Chi Mei Medical Center, Tainan, Taiwan,
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32
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Hypermethylation in Calca Promoter Inhibited ASC Osteogenic Differentiation in Rats with Type 2 Diabetic Mellitus. Stem Cells Int 2020; 2020:5245294. [PMID: 32190058 PMCID: PMC7073499 DOI: 10.1155/2020/5245294] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2019] [Accepted: 02/05/2020] [Indexed: 01/22/2023] Open
Abstract
The abnormal environment of type 2 diabetes mellitus (T2DM) leads to a substantial decrease in osteogenic function of stem cells. However, the gene sequence does not vary before and after disease for the patient. This phenomenon may be related to changes in osteogenesis-related gene expression caused by DNA methylation. In this study, we established T2DM models to extract adipose-derived stem cells (ASCs) for different gene identifications through DNA methylation sequencing. Specific fragments of methylation changes in the target gene (Calca) were identified by IGV analysis. CGRP was applied to compare the effects on ASCs-T2DM morphology via phalloidin staining, proliferation through CCK-8 assay, and osteogenic differentiation with osteogenic staining, qPCR, and repair of calvarial defect. Furthermore, 5-azacytidine (5-az) was used to intervene ASCs-T2DM to verify the relationship between the methylation level of the target fragment and expression of Calca. We found that the DNA methylation level of target fragment of Calca in ASCs-T2DM was higher than that in ASCs-C. CGRP intervention showed that it did not change the morphology of ASCs-T2DM but could improve proliferation within a certain range. Meanwhile, it could significantly enhance the formation of ALP and calcium nodules in ASCs-T2DM, increase the expression of osteogenesis-related genes in vitro, and promote the healing of calvarial defects of T2DM rat in a concentration-dependent manner. 5-az intervention indicated that the reduction of the methylation level in Calca target fragment of ASCs-T2DM indeed escalated the gene expression, which may be related to DNMT1. Taken together, the environment of T2DM could upregulate the methylation level in the promoter region of Calca and then decrease the Calca expression. The coding product of Calca revealed a promoting role for osteogenic differentiation of ASCs-T2DM. This result provides an implication for us to understand the mechanism of the decreased osteogenic ability of ASCs-T2DM and improve its osteogenic capacity.
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Parseghian CM, Napolitano S, Loree JM, Kopetz S. Mechanisms of Innate and Acquired Resistance to Anti-EGFR Therapy: A Review of Current Knowledge with a Focus on Rechallenge Therapies. Clin Cancer Res 2019; 25:6899-6908. [PMID: 31263029 PMCID: PMC6891150 DOI: 10.1158/1078-0432.ccr-19-0823] [Citation(s) in RCA: 72] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2019] [Revised: 05/16/2019] [Accepted: 06/26/2019] [Indexed: 02/06/2023]
Abstract
Innate and acquired resistance to anti-EGFR therapy (EGFRi) is a major limitation in the treatment of metastatic colorectal cancer (mCRC). Although RAS genes are the most commonly mutated innate and acquired oncogenes in cancer, there are a number of other mechanisms that limit the effectiveness of EGFRi. Patients with innate resistance have been found to contain BRAFV600E mutations, and possibly MET, MEK, PIK3CA, PTEN, and HER2 alterations. Meanwhile, BRAFV600E mutations may also be involved in acquired resistance to EGFRi, in addition to EGFR ectodomain mutations, MET alterations, and possibly HER2 amplification. In addition, paracrine effects and cell-fate mechanisms of resistance are being increasingly described as contributing to acquired resistance. Utilization of circulating tumor DNA has been paramount in monitoring the dynamic nature of acquired resistance and has helped to guide treatment decisions, particularly in the EGFRi rechallenge setting. Herein, we provide an in-depth review of EGFRi-resistance mechanisms and describe the current therapeutic landscape in the hopes of identifying effective rechallenge strategies.
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Affiliation(s)
- Christine M Parseghian
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Stefania Napolitano
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | | | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Foroughi S, Tie J, Gibbs P, Burgess AW. Epidermal growth factor receptor ligands: targets for optimizing treatment of metastatic colorectal cancer. Growth Factors 2019; 37:209-225. [PMID: 31878812 DOI: 10.1080/08977194.2019.1703702] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
The discovery of epidermal growth factor (EGF) and its receptor (EGFR) revealed the connection between EGF-like ligands, signaling from the EGFR family members and cancer. Over the next fifty years, analysis of EGFR expression and mutation led to the use of monoclonal antibodies to target EGFR in the treatment of metastatic colorectal cancer (mCRC) and this treatment has improved outcomes for patients. The use of the RAS oncogene mutational status has helped to refine patient selection for EGFR antibody therapy, but an effective molecular predictor of likely responders is lacking. This review analyzes the potential utility of measuring the expression, levels and activation of EGF-like ligands and associated processes as prognostic or predictive markers for the identification of patient risk and more effective mCRC therapies.
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Affiliation(s)
- Siavash Foroughi
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
| | - Jeanne Tie
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Medical Oncology, Peter MacCallum Cancer Centre, Melbourne, Australia
- Department of Medical Oncology, Western Health, St Albans, Australia
| | - Peter Gibbs
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Medical Oncology, Western Health, St Albans, Australia
| | - Antony Wilks Burgess
- Personalised Oncology Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Australia
- Department of Medical Biology, The University of Melbourne, Parkville, Australia
- Department of Surgery, Royal Melbourne Hospital, The University of Melbourne, Parkville, Australia
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Shi C, Xie LY, Tang YP, Long L, Li JL, Hu BL, Li KZ. Hypermethylation of N-Acetyltransferase 1 Is a Prognostic Biomarker in Colon Adenocarcinoma. Front Genet 2019; 10:1097. [PMID: 31781164 PMCID: PMC6851262 DOI: 10.3389/fgene.2019.01097] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Accepted: 10/11/2019] [Indexed: 01/05/2023] Open
Abstract
Background: The N-acetyltransferase 1 (NAT1) gene is downregulated in several cancers and associated with patient survival. In this study, we sought to examine the prognostic value and clinical significance of NAT1 methylation in colon adenocarcinoma (COAD). Methods: Data relating to NAT1 mRNA expression and methylation and clinicopathological features of COAD were extracted from the database of The Cancer Genome Atlas. We compared the mRNA expression and methylation of NAT1 between COAD and normal tissues and performed correlation analysis to assess the association between NAT1 mRNA expression and methylation. Furthermore, we assessed patient survival based on CpG sites in the promoter region of NAT1 and analyzed the association between the NAT1 mRNA expression and CpG site methylation and clinicopathological features. An independent Gene Expression Omnibus (GEO) dataset was used to validate the results. Results: We found that the expression of NAT1 mRNA was reduced in COAD compared with normal tissues and that mean methylation of the eight CpG sites in the promoter region of NAT1 was higher in COAD tissues than in normal tissues. Furthermore, five CpG sites were demonstrated to be significantly negatively correlated with NAT1 mRNA expression in COAD. Survival analysis indicated that NAT1 mRNA expression and the cg15797286 and cg18509990 sites were associated with the overall survival of COAD patients. Combined survival analysis revealed that combinations of NAT1 mRNA expression with five CpG sites were significantly associated with the overall survival of COAD patients. Both NAT1 mRNA and cg15797286 were associated with the T, N, and clinical stages of COAD. The GEO data indicated that cg15797286 was hypermethylated in recurrent colorectal adenomas. Conclusions: Methylation of NAT1 is associated with the development of COAD, and may serve as prognostic and treatment biomarkers for COAD.
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Affiliation(s)
- Cheng Shi
- Department of Gastroenterology, The People's Hospital of Liuzhou, Liuzhou, China
| | - Li-Ye Xie
- Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Yan-Ping Tang
- Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Long Long
- Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Ji-Lin Li
- Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Bang-Li Hu
- Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Ke-Zhi Li
- Department of Research, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
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Grassadonia A, Di Marino P, Ficorella C, Cortellini A, Cannita K, Parisi A, Gamucci T, Zoratto F, Vici P, Barba M, Porreca E, Neri M, Veronese A, Natoli C, De Tursi M, Tinari N. Impact of primary tumor location in patients with RAS wild-type metastatic colon cancer treated with first-line chemotherapy plus anti-EGFR or anti-VEGF monoclonal antibodies: a retrospective multicenter study. J Cancer 2019; 10:5926-5934. [PMID: 31762802 PMCID: PMC6856567 DOI: 10.7150/jca.34550] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2019] [Accepted: 07/01/2019] [Indexed: 12/24/2022] Open
Abstract
Emerging evidence supports a prognostic role of primary tumor location in metastatic colon cancer (mCC). We conducted a retrospective analysis to evaluate the effect of tumor location on prognosis and efficacy of biological agents (anti-EGFR, Cetuximab and Panitumumab, or anti-VEGF, Bevacizumab) added to first-line chemotherapy in patients with RAS wild-type (wt) mCC. Patients with newly diagnosed RAS wt mCC candidates to first-line chemotherapy with anti-EGFRs or Bevacizumab were selected. Clinical outcomes were assessed and stratified by tumor location and type of treatment. Overall, 351 patients met the inclusion criteria. Primary colon cancer was right-sided (RCC) in 105 (29.9%) patients and left-sided (LCC) in 246 (70.1%). Patients with LCC had a better OS compared to those with RCC (33.6 vs 23.5 months, HR 0.74; 95% CI, 0.55 to 0.99; p=0.049). In the overall study population, OS was not significantly different for patients treated with Cetuximab or Panitumumab as compared to those receiving Bevacizumab. However, when comparing treatment outcome according to tumor sidedness, patients with LCC treated with Cetuximab or Panitumumab had a significantly longer PFS (12.4 vs 10.7 months; HR: 0.69; 95% CI, 0.51 to 0.93; p= 0.015) and OS (40.7 vs 28.6 months; HR: 0.67; 95% CI 0.47 to 0.95; p= 0.026). No relevant differences were observed in patients with RCC. We found evidence in support of the impact of tumor location in RAS wt mCC treated with first-line chemotherapy in association with targeted therapy. More favorable outcomes were observed in LCC patients, but not in RCC patients, treated with anti-EGFR agents compared with those who received Bevacizumab. Further, prospective and adequately sized studies are warranted to confirm our findings.
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Affiliation(s)
- Antonino Grassadonia
- Department of Medical, Oral & Biotechnological Sciences and CeSI-MeT, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Pietro Di Marino
- Department of Medical, Oral & Biotechnological Sciences, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Corrado Ficorella
- Medical Oncology Unit, St Salvatore Hospital, Department of Biotechnological & Applied Clinical Sciences, University of L'Aquila, Via Vetoio, 67100, L'Aquila, Italy
| | - Alessio Cortellini
- Medical Oncology Unit, St Salvatore Hospital, Department of Biotechnological & Applied Clinical Sciences, University of L'Aquila, Via Vetoio, 67100, L'Aquila, Italy
| | - Katia Cannita
- Medical Oncology Unit, St Salvatore Hospital, Department of Biotechnological & Applied Clinical Sciences, University of L'Aquila, Via Vetoio, 67100, L'Aquila, Italy
| | - Alessandro Parisi
- Medical Oncology Unit, St Salvatore Hospital, Department of Biotechnological & Applied Clinical Sciences, University of L'Aquila, Via Vetoio, 67100, L'Aquila, Italy
| | - Teresa Gamucci
- Medical Oncology Unit, Sandro Pertini Hospital, Rome, Italy
| | | | - Patrizia Vici
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Maddalena Barba
- Division of Medical Oncology 2, IRCCS Regina Elena National Cancer Institute, Rome, Italy
| | - Ettore Porreca
- Department of Medical, Oral & Biotechnological Sciences, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Matteo Neri
- Department of Medicine and Ageing Sciences and CeSI-MeT, G. D'Annunzio University, Chieti, Italy
| | - Angelo Veronese
- Department of Medicine and Ageing Sciences and CeSI-MeT, G. D'Annunzio University, Chieti, Italy
| | - Clara Natoli
- Department of Medical, Oral & Biotechnological Sciences and CeSI-MeT, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Michele De Tursi
- Department of Medical, Oral & Biotechnological Sciences, G. D'Annunzio University, Chieti-Pescara, Italy
| | - Nicola Tinari
- Department of Medical, Oral & Biotechnological Sciences and CeSI-MeT, G. D'Annunzio University, Chieti-Pescara, Italy
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Du Z, Liu X, Chen T, Gao W, Wu Z, Hu Z, Wei D, Gao C, Li Q. Targeting a Sirt5-Positive Subpopulation Overcomes Multidrug Resistance in Wild-Type Kras Colorectal Carcinomas. Cell Rep 2019. [PMID: 29514096 DOI: 10.1016/j.celrep.2018.02.037] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
A major obstacle for successful management of patients with colorectal carcinoma (CRC) is resistance to anti-cancer cytotoxic treatments. Here, we identified a mechanism of multidrug resistance in wild-type Kras CRCs based on the survival of a cell subpopulation characterized by Sirt5 expression. Sirt5+ cells in wild-type Kras CRCs are resistant to either chemotherapeutic agents or cetuximab and serve as a reservoir for recurrence. Sirt5 demalonylates and inactivates succinate dehydrogenase complex subunit A (SDHA), leading to an accumulation of the oncometabolite succinate. Succinate binds to and activates a reactive oxygen species-scavenging enzyme, thioredoxin reductase 2 (TrxR2), to confer chemotherapy resistance. In contrast, Sirt5+ cells exhibit an elevated succinate-to-aKG ratio that inhibits aKG-dependent dioxygenases to maintain cetuximab resistance. Our findings suggest that Sirt5 inhibitors in combination with chemotherapeutic agents and/or cetuximab may represent a therapeutic strategy for CRC patients harboring wild-type Kras.
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Affiliation(s)
- ZunGuo Du
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China; Department of Pathology, HuaShan Hospital, Fudan University, Shanghai 200040, China
| | - XiuJuan Liu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - Tao Chen
- Endoscopy Center, ZhongShan Hospital, Fudan University, Shanghai 200032, China
| | - WenChao Gao
- Department of General Surgery, ChangZheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - ZhengMing Wu
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | - ZhiQian Hu
- Department of General Surgery, ChangZheng Hospital, Second Military Medical University, Shanghai 200003, China
| | - Dong Wei
- Department of Anus and Intestine Surgery, PLA Central Hospital 150, Luoyang 471003, Henan, China
| | - ChunFang Gao
- Department of Anus and Intestine Surgery, PLA Central Hospital 150, Luoyang 471003, Henan, China
| | - QingQuan Li
- Department of Pathology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
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Cai Y, Xie KL, Wu HL, Wu K. Functional suppression of Epiregulin impairs angiogenesis and aggravates left ventricular remodeling by disrupting the extracellular-signal-regulated kinase1/2 signaling pathway in rats after acute myocardial infarction. J Cell Physiol 2019; 234:18653-18665. [PMID: 31062344 DOI: 10.1002/jcp.28503] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2018] [Revised: 02/21/2019] [Accepted: 03/06/2019] [Indexed: 11/11/2022]
Abstract
Acute myocardial infarction (AMI), a severe consequence of coronary atherosclerotic heart disease, is often associated with high mortality and morbidity. Emerging evidence have shown that the inhibition of the extracellular-signal-regulated kinase (ERK) signaling pathway appears to protect against AMI. Epiregulin (EREG) is an autocrine growth factor that is believed to activate the MEK/ERK signaling pathway. Therefore, the aim of the present study was to determine the expression patterns of EREG in AMI and to further study its effects on AMI induced experimentally in rats focusing on angiogenesis and left ventricular remodeling. Microarray-based gene expression profiling of AMI was used to identify differentially expressed genes. To understand the biological significance of EREG and whether it is involved in AMI disease through the ERK1/2 signaling pathway, rats after AMI were treated with small interfering RNA (siRNA) against EREG, an ERK1/2 pathway inhibitor, PD98059, or both of them. The microarray data sets GSE66360 and GSE46395 showed that EREG was robustly induced in AMI. Both siRNA-mediated depletion of EREG and PD98059 treatment were shown to significantly increase infarct size and left ventricular cardiomyocyte loss and enhance left ventricular remodeling. In addition, we also found that the ERK1/2 signaling pathway was inhibited following siRNA-mediated EREG inhibition and PD98059 could enhance the effects of EREG inhibition on AMI. In conclusion, these findings highlight that the silencing of EREG inhibits angiogenesis and promotes left ventricular remodeling by disrupting the ERK1/2 signaling pathway, providing a novel therapeutic target for limiting AMI.
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Affiliation(s)
- Ying Cai
- Department of Rehabilitation, Xiangya Hospital, Central South University, Changsha, P.R. China
| | - Kang-Ling Xie
- Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Huan-Lin Wu
- Second School of Clinical Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Kai Wu
- Department of Rehabilitation, Xiangya Hospital, Central South University, Changsha, P.R. China
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Ibrahim J, Op de Beeck K, Fransen E, Croes L, Beyens M, Suls A, Vanden Berghe W, Peeters M, Van Camp G. Methylation analysis of Gasdermin E shows great promise as a biomarker for colorectal cancer. Cancer Med 2019; 8:2133-2145. [PMID: 30993897 PMCID: PMC6536921 DOI: 10.1002/cam4.2103] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 03/05/2019] [Accepted: 03/05/2019] [Indexed: 12/17/2022] Open
Abstract
In addition to its implication in hereditary hearing loss, the Gasdermin E (GSDME) gene is also a tumor suppressor involved in cancer progression through programmed cell death. GSDME epigenetic silencing through methylation has been shown in some cancer types, but studies are yet to fully explore its diagnostic/prognostic potential in colorectal cancer on a large-scale. We used public data from The Cancer Genome Atlas (TCGA) to investigate differences in GSDME methylation and expression between colorectal cancer and normal colorectal tissue, and between left- and right-sided colorectal cancers in 432 samples. We also explored GSDME's diagnostic capacity as a biomarker for colorectal cancer. We observed differential methylation in all 22 GSDME CpGs between tumor and normal tissues, and in 18 CpGs between the left- and right-sided groups. In the cancer tissue, putative promoter probes were hypermethylated and gene body probes were hypomethylated, while this pattern was inversed in normal tissues. Both putative promoter and gene body CpGs correlated well together but formed distinct methylation patterns with the putative promoter exhibiting the most pronounced methylation differences between tumor and normal tissues. Clinicopathological parameters, excluding age, did not show any effect on CpG methylation. Although the methylation of 5 distinct probes was a good predictor of gene expression, we could not identify an association between GSDME methylation and expression in general. Survival analysis showed no association between GSDME methylation and expression on 5-year patient survival. Through logistic regression, we identified a combination of 2 CpGs, that can discriminate between cancer and normal tissue with high accuracy (AUC = 0.95) irrespective of age and tumor stage. We also validated our model in 3 external methylation datasets, from the Gene Expression Omnibus database, and similar results were reached. Our results suggest that GSDME is a promising biomarker for the detection of colorectal cancer.
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Affiliation(s)
- Joe Ibrahim
- Centre of Medical GeneticsUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
- Centre for Oncological ResearchUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
| | - Ken Op de Beeck
- Centre of Medical GeneticsUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
- Centre for Oncological ResearchUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
| | - Erik Fransen
- Centre of Medical GeneticsUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
- StatUa Centre for StatisticsUniversity of AntwerpAntwerpBelgium
| | - Lieselot Croes
- Centre of Medical GeneticsUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
- Centre for Oncological ResearchUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
| | - Matthias Beyens
- Centre of Medical GeneticsUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
- Centre for Oncological ResearchUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
| | - Arvid Suls
- Centre of Medical GeneticsUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
| | - Wim Vanden Berghe
- Laboratory of Protein Chemistry, Proteomics and Epigenetic Signaling, Department of Biomedical SciencesUniversity of AntwerpAntwerpBelgium
| | - Marc Peeters
- Centre for Oncological ResearchUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
- Department of Medical OncologyAntwerp University HospitalEdegemBelgium
| | - Guy Van Camp
- Centre of Medical GeneticsUniversity of Antwerp and Antwerp University HospitalEdegemBelgium
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Aderka D, Stintzing S, Heinemann V. Explaining the unexplainable: discrepancies in results from the CALGB/SWOG 80405 and FIRE-3 studies. Lancet Oncol 2019; 20:e274-e283. [DOI: 10.1016/s1470-2045(19)30172-x] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2019] [Revised: 02/27/2019] [Accepted: 03/04/2019] [Indexed: 02/06/2023]
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Innocenti F, Ou FS, Qu X, Zemla TJ, Niedzwiecki D, Tam R, Mahajan S, Goldberg RM, Bertagnolli MM, Blanke CD, Sanoff H, Atkins J, Polite B, Venook AP, Lenz HJ, Kabbarah O. Mutational Analysis of Patients With Colorectal Cancer in CALGB/SWOG 80405 Identifies New Roles of Microsatellite Instability and Tumor Mutational Burden for Patient Outcome. J Clin Oncol 2019; 37:1217-1227. [PMID: 30865548 DOI: 10.1200/jco.18.01798] [Citation(s) in RCA: 233] [Impact Index Per Article: 38.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE CALGB/SWOG 80405 was a randomized phase III trial that found no statistically significant difference in overall survival (OS) in patients with first-line metastatic colorectal cancer treated with chemotherapy plus either bevacizumab or cetuximab. Primary tumor DNA from 843 patients has been used to discover genetic markers of OS. PATIENTS AND METHODS Gene mutations were determined by polymerase chain reaction. Microsatellite status was determined by genotyping of microsatellites. Tumor mutational burden (TMB) was determined by next-generation sequencing. Cox proportional hazard models were used, with adjusting factors. Interaction of molecular alterations with either the bevacizumab or the cetuximab arms was tested. RESULTS Patients with high TMB in their tumors had longer OS than did patients with low TMB (hazard ratio [HR], 0.73 [95% CI, 0.57 to 0.95]; P = .02). In patients with microsatellite instability-high (MSI-H) tumors, longer OS was observed in the bevacizumab arm than in the cetuximab arm (HR, 0.13 [95% CI, 0.06 to 0.30]; interaction P < .001 for interaction between microsatellite status and the two arms). Patients with BRAF mutant tumors had shorter OS than did patients with wild-type (WT) tumors (HR, 2.01 [95% CI, 1.49 to 2.71]; P < .001). Patients with extended RAS mutant tumors had shorter OS than did patients with WT tumors (HR, 1.52 [95% CI, 1.26 to 1.84]; P < .001). Patients with triple-negative tumors (WT for NRAS/KRAS/BRAF) had a median OS of 35.9 months (95% CI, 33.0 to 38.8 months) versus 22.2 months (95% CI, 19.6 to 24.4 months ) in patients with at least one mutated gene in their tumors (P < .001). CONCLUSION In patients with metastatic colorectal cancer treated in first line, low TMB, and BRAF and RAS mutations are negative prognostic factors. Patients with MSI-H tumors benefited more from bevacizumab than from cetuximab, and studies to confirm this effect of MSI-H are warranted.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Hanna Sanoff
- 1 University of North Carolina at Chapel Hill, Chapel Hill, NC
| | - James Atkins
- 8 Southeast Clinical Oncology Research Consortium, Winston-Salem, NC
| | - Blasé Polite
- 9 University of Chicago Comprehensive Cancer Center, Chicago, IL
| | - Alan P Venook
- 10 University of California San Francisco, San Francisco, CA
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Steponaitis G, Kazlauskas A, Skiriute D, Vaitkiene P, Skauminas K, Tamasauskas A. Significance of Amphiregulin (AREG) for the Outcome of Low and High Grade Astrocytoma Patients. J Cancer 2019; 10:1479-1488. [PMID: 31031857 PMCID: PMC6485216 DOI: 10.7150/jca.29282] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 12/05/2018] [Indexed: 12/31/2022] Open
Abstract
Background: Amphiregulin (AREG) is one of the ligands of the epidermal growth factor receptor which levels was shown to have a tight coherence with various types of cancer. AREG was also designated to be a promising marker for several types of cancer however precious little data about AREG role in the most frequent and generally lethal human brain tumours - astrocytomas reported up to date. The aim of the study was to investigate how AREG changes at epigenetic and expression levels reflect on astrocytoma malignancy and patient outcome. Methods: In total 205 low and high grade astrocytoma samples (15 pilocytic astrocytomas, 56 diffuse astrocytomas, 32 anaplastic astrocytomas and 102 glioblastomas) were used for target mRNA, protein expression and DNA methylation analysis applying qRT-PCR, Western-Blot and MS-PCR assays, respectively. Results: Present research revealed that AREG expression level and methylation in cancer tissue is dependent on the grade of astrocytoma. GBM tissue disclosed elevated AREG mRNA expression but reduced AREG protein level as compared to grade II and grade III astrocytomas (p<0.001). Increased methylation frequency was also more abundant in GBM (74%) than grade I, II and III astrocytomas (25%, 34%, and 36%, respectively). The survival analysis revealed relevant differences in patient overall survival between AREG methylation, mRNA and protein expression groups. Kaplan-Meier analysis encompassing only malignant tumours showed similar results indicating that AREG is associated with astrocytoma patient survival independently from astrocytoma grade. Conclusions: Current findings demonstrate that AREG appearance is associated with patient survival as well as astrocytomas malignancy indicating its influence on tumour progression and suggest its applicability as a promising marker.
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Affiliation(s)
- Giedrius Steponaitis
- Laboratory of Molecular Neurooncology, Neuroscience Institute, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, LT 50161, Lithuania
| | - Arunas Kazlauskas
- Laboratory of Molecular Neurooncology, Neuroscience Institute, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, LT 50161, Lithuania
| | - Daina Skiriute
- Laboratory of Molecular Neurooncology, Neuroscience Institute, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, LT 50161, Lithuania
| | - Paulina Vaitkiene
- Laboratory of Molecular Neurooncology, Neuroscience Institute, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, LT 50161, Lithuania
| | - Kestutis Skauminas
- Laboratory of Molecular Neurooncology, Neuroscience Institute, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, LT 50161, Lithuania
| | - Arimantas Tamasauskas
- Laboratory of Molecular Neurooncology, Neuroscience Institute, Lithuanian University of Health Sciences, Eiveniu str. 4, Kaunas, LT 50161, Lithuania
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Ochiai T, Nishimura K, Watanabe T, Kitajima M, Nakatani A, Nagayasu K, Sakuyama N, Sato T, Kishine K, Abe Y, Nagaoka I. Impact of primary tumor location as a predictive factor in patients suffering from colorectal cancer treated with cytotoxic anticancer agents based on the collagen gel droplet-embedded drug sensitivity test. Oncol Lett 2019; 17:1842-1850. [PMID: 30675246 PMCID: PMC6341756 DOI: 10.3892/ol.2018.9805] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2018] [Accepted: 11/20/2018] [Indexed: 12/18/2022] Open
Abstract
In recent studies, better clinical outcomes for patients with left-sided colon cancer (CC) compared with right-sided CC have been reported; however, in such investigations, the chemotherapy regimens included molecular-targeting agents. To the best of our knowledge, the impact of primary tumor location as a predictive factor in patients suffering from CC treated with cytotoxic anticancer agents alone has not been investigated. The aim of the present study was to determine the impact of the primary tumor location as a predictive factor of patients undergoing the following cytotoxic anticancer agent regimens: Leucovorin and fluorouracil + oxaliplatin (FOLFOX) or Leucovorin and fluorouracil + irinotecan (FOLFIRI), using the collagen gel droplet-embedded drug sensitivity test (CD-DST). Between March 2008 and April 2017, tumor specimens were obtained from 133 patients suffering from colorectal cancer (CRC) who had not received preoperative chemotherapy. CD-DST was performed and the growth inhibition rate (IR) was determined in FOLFOX and FOLFIRI regimens. The associations between tumor location and IR values for each condition were evaluated. In the present study, the prognosis of patients receiving palliative chemotherapy as well as treatment with molecularly-targeted agents was also investigated. There were no significant differences in the IRs (%) of the two regimens using CD-DST for right-sided tumors compared with left-sided tumors, including or excluding the rectum. The median survival times of patients with right CC and left CC who had received palliative chemotherapy and treatment with molecularly-targeted agents were 960 and 1,348 days, respectively. Primary tumor location did not represent a predictive factor for the efficacy of treatment with cytotoxic anticancer agent regimens using CD-DST. However, patients suffering from left-sided CC were revealed to exhibit better clinical outcomes compared with patients suffering from right-sided CC when molecularly-targeted agent regimens were administered. Therefore, the results of the present study suggested that molecularly-targeted agents rather than cytotoxic anticancer agents may result in improved clinical outcomes for patients with CRC suffering from left-sided tumors.
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Affiliation(s)
- Takumi Ochiai
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Kazuhiko Nishimura
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Tomoo Watanabe
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Masayuki Kitajima
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Akinori Nakatani
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Kiichi Nagayasu
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Naoki Sakuyama
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Tsuyoshi Sato
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Kenji Kishine
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Yu Abe
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Isao Nagaoka
- Department of Host Defense and Biochemical Research, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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Kim K, Castro EJT, Shim H, Advincula JVG, Kim YW. Differences Regarding the Molecular Features and Gut Microbiota Between Right and Left Colon Cancer. Ann Coloproctol 2018; 34:280-285. [PMID: 30630301 PMCID: PMC6347335 DOI: 10.3393/ac.2018.12.17] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2018] [Accepted: 12/17/2018] [Indexed: 12/22/2022] Open
Abstract
For many years, developmental and physiological differences have been known to exist between anatomic segments of the colorectum. Because of different outcomes, prognoses, and clinical responses to chemotherapy, the distinction between right colon cancer (RCC) and left colon cancer (LCC) has gained attention. Furthermore, variations in the molecular features and gut microbiota between right and LCCs have recently been a hot research topic. CpG island methylator phenotype-high, microsatellite instability-high colorectal cancers are more likely to occur on the right side whereas tumors with chromosomal instability have been detected in approximately 75% of LCC patients and 30% of RCC patients. The mutation rates of oncogenes and tumor suppressor genes also differ between RCC and LCC patients. Biofilm is more abundant in RCC patients than LLC patients, as are Prevotella, Selenomonas, and Peptostreptococcus. Conversely, Fusobacterium, Escherichia/Shigella, and Leptotrichia are more abundant in LCC patients compared to RCC patients. Distinctive characteristics are apparent in terms of molecular features and gut microbiota between right and LCC. However, how or to what extent these differences influence diverging oncologic outcomes remains unclear. Further clinical and translational studies are needed to elucidate the causative relationship between primary tumor location and prognosis.
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Affiliation(s)
- Kwangmin Kim
- Big Data Research Group, Yonsei University Wonju College of Medicine, Wonju, Korea.,Division of Acute Care Surgery, Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Korea
| | | | - Hongjin Shim
- Division of Trauma Surgery and Surgical Critical Care, Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Korea
| | | | - Young-Wan Kim
- Big Data Research Group, Yonsei University Wonju College of Medicine, Wonju, Korea.,Division of Colorectal Surgery, Department of Surgery, Yonsei University Wonju College of Medicine, Wonju, Korea
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Barresi V, Cinnirella G, Valenti G, Spampinato G, Musso N, Castorina S, Condorelli DF. Gene expression profiles in genome instability-based classes of colorectal cancer. BMC Cancer 2018; 18:1265. [PMID: 30563495 PMCID: PMC6299572 DOI: 10.1186/s12885-018-5174-z] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2018] [Accepted: 12/03/2018] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Broad copy number aberrations (BCNAs) represent a common form of genome instability in colorectal cancer (CRC). CRCs show large variations in their level of aneuploidy: microsatellite-instable (MSI) tumors are known to have a near-diploid karyotype while microsatellite-stable (MSS) tumors show high level of chromosomal instability. However, MSS tumors have great heterogeneity in the number of BCNAs, with a minor percentage of samples showing an almost normal karyotype. In the present work we subdivided MSS CRCs according to a "BCNA score" and characterized their transcriptome profiles, considered as a proxy to their phenotypic features. METHODS Microsatellite testing, genome-wide DNA copy number and whole-transcript expression analysis (HTA) were performed on 33 tumor samples and 25 normal colonic tissue samples from 32 CRC patients. 15.1% of the samples were MSI tumors (n = 5), whereas 84.9% were MSS tumors (n = 28). Gene expression data of 34 additional MSI tumors was retrieved from a public functional genomics data repository. RESULTS Using as a threshold the first quartile of the BCNA score distribution, MSS samples were classified as low-BCNA (LB, n = 7) or high-BCNA (HB, n = 21). LB tumors were enriched for mucinous CRCs and their gene-expression profile resembled that of MSI samples for what concerns a subset of genes involved in secretory processes, mucosal protection, and extracellular matrix remodeling. HB tumors were predominantly non-mucinous adenocarcinomas and showed overexpression of a subset of genes typical of surface colonocytes and EGF signaling. A large percentage of unclassified samples according to the consensus molecular subtypes (CMS) classifier was found in the LB group (43%), whereas 76% HB tumors belonged to CMS2. CONCLUSIONS A classification of colorectal tumors based on the number of BCNAs identifies two groups of MSS tumors which differ for histopathology and gene expression profile. Such information can be exploited for its translational relevance in different aspects of CRC clinical management.
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Affiliation(s)
- Vincenza Barresi
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
- Laboratory of Complex Systems, Scuola Superiore di Catania, University of Catania, Catania, Italy
| | - Giacomo Cinnirella
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
| | - Giovanna Valenti
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
| | - Giorgia Spampinato
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
| | - Nicolò Musso
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
| | - Sergio Castorina
- Department of Surgical Medical Sciences and Advanced Technologies “G. F. Ingrassia”, University of Catania, Catania, Italy
- Fondazione Mediterranea G.B. Morgagni, Catania, Italy
| | - Daniele F. Condorelli
- Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Viale Santa Sofia 89-97, 95123 Catania, Italy
- Laboratory of Complex Systems, Scuola Superiore di Catania, University of Catania, Catania, Italy
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Vacante M, Borzì AM, Basile F, Biondi A. Biomarkers in colorectal cancer: Current clinical utility and future perspectives. World J Clin Cases 2018; 6:869-881. [PMID: 30568941 PMCID: PMC6288499 DOI: 10.12998/wjcc.v6.i15.869] [Citation(s) in RCA: 106] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Revised: 10/30/2018] [Accepted: 11/07/2018] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is a major cause of cancer death worldwide. CRC has poor prognosis and there is a crucial need for new diagnostic and prognostic biomarkers to avoid CRC-related deaths. CRC can be considered a sporadic disease in most cases (75%-80%), but it has been suggested that crosstalk between gene mutations (i.e., mutations of BRAF, KRAS, and p53 as well as microsatellite instability) and epigenetic alterations (i.e., DNA methylation of CpG island promoter regions) could play a pivotal role in cancer development. A number of studies have focused on molecular testing to guide targeted and conventional treatments for patients with CRC, sometimes with contrasting results. Some of the most useful innovations in the management of CRC include the possibility to detect the absence of KRAS, BRAF, NRAS and PIK3CA gene mutations with the subsequent choice to administer targeted adjuvant therapy with anti-epidermal growth factor receptor antibodies. Moreover, CRC patients can benefit from tests for microsatellite instability and for the detection of loss of heterozygosity of chromosome 18q that can be helpful in guiding therapeutic decisions as regards the administration of 5-FU. The aim of this review was to summarize the most recent evidence on the possible use of genetic or epigenetic biomarkers for diagnosis, prognosis and response to therapy in CRC patients.
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Affiliation(s)
- Marco Vacante
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Antonio Maria Borzì
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Francesco Basile
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
| | - Antonio Biondi
- Department of General Surgery and Medical-Surgical Specialties, University of Catania, Catania 95123, Italy
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47
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Ochiai T, Nishimura K, Watanabe T, Kitajima M, Nakatani A, Nagayasu K, Sakuyama N, Sato T, Kishine K, Abe Y, Nagaoka I. Impact of primary tumor location as a predictive factor in patients suffering from colorectal cancer treated with cytotoxic anticancer agents based on the collagen gel droplet-embedded drug sensitivity test. Oncol Lett 2018; 14:6045-6052. [PMID: 30675246 DOI: 10.3892/ol.2017.6960] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2016] [Accepted: 02/23/2017] [Indexed: 12/17/2022] Open
Abstract
In recent studies, better clinical outcomes for patients with left-sided colon cancer (CC) compared with right-sided CC have been reported; however, in such investigations, the chemotherapy regimens included molecular-targeting agents. To the best of our knowledge, the impact of primary tumor location as a predictive factor in patients suffering from CC treated with cytotoxic anticancer agents alone has not been investigated. The aim of the present study was to determine the impact of the primary tumor location as a predictive factor of patients undergoing the following cytotoxic anticancer agent regimens: Leucovorin and fluorouracil + oxaliplatin (FOLFOX) or Leucovorin and fluorouracil + irinotecan (FOLFIRI), using the collagen gel droplet-embedded drug sensitivity test (CD-DST). Between March 2008 and April 2017, tumor specimens were obtained from 133 patients suffering from colorectal cancer (CRC) who had not received preoperative chemotherapy. CD-DST was performed and the growth inhibition rate (IR) was determined in FOLFOX and FOLFIRI regimens. The associations between tumor location and IR values for each condition were evaluated. In the present study, the prognosis of patients receiving palliative chemotherapy as well as treatment with molecularly-targeted agents was also investigated. There were no significant differences in the IRs (%) of the two regimens using CD-DST for right-sided tumors compared with left-sided tumors, including or excluding the rectum. The median survival times of patients with right CC and left CC who had received palliative chemotherapy and treatment with molecularly-targeted agents were 960 and 1,348 days, respectively. Primary tumor location did not represent a predictive factor for the efficacy of treatment with cytotoxic anticancer agent regimens using CD-DST. However, patients suffering from left-sided CC were revealed to exhibit better clinical outcomes compared with patients suffering from right-sided CC when molecularly-targeted agent regimens were administered. Therefore, the results of the present study suggested that molecularly-targeted agents rather than cytotoxic anticancer agents may result in improved clinical outcomes for patients with CRC suffering from left-sided tumors.
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Affiliation(s)
- Takumi Ochiai
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Kazuhiko Nishimura
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Tomoo Watanabe
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Masayuki Kitajima
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Akinori Nakatani
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Kiichi Nagayasu
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Naoki Sakuyama
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Tsuyoshi Sato
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Kenji Kishine
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Yu Abe
- Department of Surgery, Tobu Chiiki Hospital, Tokyo Metropolitan Health and Medical Treatment Corporation, Tokyo 125-8512, Japan
| | - Isao Nagaoka
- Department of Host Defense and Biochemical Research, Juntendo University School of Medicine, Tokyo 113-8421, Japan
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Khan M, Loree JM, Advani SM, Ning J, Li W, Pereira AAL, Lam M, Raghav K, Morris VK, Broaddus R, Maru D, Overman MJ, Kopetz S. Prognostic Implications of Mucinous Differentiation in Metastatic Colorectal Carcinoma Can Be Explained by Distinct Molecular and Clinicopathologic Characteristics. Clin Colorectal Cancer 2018; 17:e699-e709. [PMID: 30205948 PMCID: PMC6588353 DOI: 10.1016/j.clcc.2018.07.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2018] [Revised: 07/09/2018] [Accepted: 07/11/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND The mucinous histologic subtype accounts for 5% to 20% of colorectal cancer (CRC) cases but remains poorly characterized. The present study characterized the baseline characteristics, mutational profile, and clinical outcomes of patients diagnosed with mucinous CRC. MATERIALS AND METHODS We identified 1877 patients with metastatic CRC with available histologic findings and molecular profiling and summarized the baseline clinical and pathologic characteristics and overall survival (OS) stratified by the histologic type. The data from separate cohorts with consensus molecular subtype (CMS) and CpG island methylator information were also summarized. RESULTS The mucinous histologic type was found in 277 of the 1877 patients (14.8%) and was associated with an increased prevalence of microsatellite instability (P < .001) and a right-sided primary (P < .001). An increased frequency of CMS1 (microsatellite instability immune) and lower rates of CMS2 (canonical) were identified, with mucinous compared with nonmucinous adenocarcinoma (P < .0001). Mutations in SMAD4 (P < .001), GNAS (P < .001), ERBB2 (P = .02), BRAF (P < .001), and KRAS (P < .001) occurred at greater frequencies in the mucinous CRC cases, and TP53 (P < .001), APC (P < .001), and NRAS mutations (P = .03) were less common. Univariate (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.17-1.63; P < .001) and multivariate analysis (HR, 1.36; 95% CI, 1.12-1.64; P = .002) demonstrated that the mucinous histologic type is associated with worse OS. The features associated with the mucinous histologic subtype were independent predictors for shorter OS, including BRAF (HR, 1.74; 95% CI, 1.35-2.25; P < .001) and KRAS (HR, 1.42; 95% CI, 1.22-1.65; P < .001) mutations, right-sided location (HR, 1.20; 95% CI, 1.04-1.39; P = .01), and synchronous metastases (HR, 2.92; 95% CI, 2.49-3.42; P < .001). CONCLUSION Compared with nonmucinous adenocarcinoma, the mucinous histologic type is associated with a worse prognosis, even when controlling for known prognostic features. This unique biologic behavior should be considered in the treatment and prognostic assessment of patients with CRC.
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Affiliation(s)
- Maliha Khan
- Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Jonathan M Loree
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Shailesh M Advani
- Department of Oncology, Georgetown Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC
| | - Jing Ning
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Wen Li
- Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Allan A L Pereira
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael Lam
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Kanwal Raghav
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Van K Morris
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Russell Broaddus
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Dipen Maru
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Michael J Overman
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
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Hu Y, Tao SY, Deng JM, Hou ZK, Liang JQ, Huang QG, Li LH, Li HB, Chen YM, Yi H, Chen XL, Liu H. Prognostic Value of NRAS Gene for Survival of Colorectal Cancer Patients: A Systematic Review and Meta-Analysis. Asian Pac J Cancer Prev 2018; 19:3001-3008. [PMID: 30484984 PMCID: PMC6318417 DOI: 10.31557/apjcp.2018.19.11.3001] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 10/20/2018] [Indexed: 12/12/2022] Open
Abstract
Introduction: NRAS gene is associated with malignant proliferation and metastasis of colorectal cancer (CRC). But its prognostic value on CRC is still unknown. The objective of this study is to perform a meta-analysis to obtain its prognostic value on survival of CRC patients. Methods: The systematic review and meta-analysis was designed, undertaken and reported using items from the PRISMA statement. Relevant articles were identified through PubMed (containing Medline), Embase, Web of Science databases and Google scholar search engines from their inception up to October 3, 2016. The articles about NRAS on prognosis of CRC patients were enrolled. The association between NRAS and CRC survival time (including overall survival [OS], progression-free survival [PFS], and disease-free survival [DFS]) was evaluated using hazard ratio (HR) with its corresponding 95% confidence interval (CI). Results: A total of fifteen articles were included. High-expression of NRAS was significantly associated with poor OS (HR: 1.36, 95% CI: 1.15–1.61), and poor PFS (HR: 1.75, 95% CI: 1.04–2.94). The combined HR of NRAS on DFS was 0.87 (95% CI: 0.37–2.03). Subgroup analysis showed that NRAS was significantly associated with poor OS for patients from Western countries (HR: 1.38, 95% CI: 1.09–1.73), but not for those from Asian countries. Conclusions: This meta-analysis demonstrate that NRAS gene could predict the poor prognosis for the CRC patients. More large-sample cohort studies are needed to further confirm this conclusion.
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Affiliation(s)
- Yue Hu
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Shuang-You Tao
- Spleen and Stomach Institute, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jie-Min Deng
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zheng-Kun Hou
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jia-Qi Liang
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Qiu-Gu Huang
- The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Liang-Hui Li
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui-Biao Li
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yi-Ming Chen
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hua Yi
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xin-Lin Chen
- School of Basic Medical Science, Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Hui Liu
- The Third Affiliated Hospital, Guangzhou University of Chinese Medicine, Guangzhou, China
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50
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Abstract
Colorectal cancer (CRC) is a heterogeneous disease, and the search for clinical and molecular prognostic and predictive factors is thus necessary to better tailor each individual patient's management. Primary tumor location (PTL) seems to act as a master prognostic factor pooling different clinical, pathological, and molecular poor prognostic factors. In fact, right-sided (RS) CRC patients are more frequently female and elderly with microsatellite unstable, BRAF mutated, CpG island methylator phenotype (CIMP)-high, poorly differentiated tumors, compared to left-sided (LS) CRC patients. PTL does not seem to clearly influence disease-free survival (DFS) in localised colon cancer even though the opposite prognostic value of RS tumors on DFS depending on RAS/BRAF mutational status has been recently suggested in these patients. In metastatic CRC (mCRC), the poor prognosis associated with RS tumors is confirmed in the most recent publications in the era of double and triple chemotherapeutic regimens and targeted agents. Concerning the predictive value of PTL, in patients with RAS wild-type mCRC in the first-line setting, anti-epidermal growth factor receptor (EGFR) therapy combined with chemotherapy appears to be more effective than bevacizumab in LS CRC, while patients with RS CRC benefit less from anti-EGFR therapy, and intensive chemotherapy plus bevacizumab may be more appropriate but EGFR antibodies remain an option if objective response is needed. Due to the limitation of the current data (unplanned and retrospective analyses), these conclusions must be interpreted with caution. Clinical trials in RS CRC may be of interest to clarify what is the best treatment strategy in these patients.
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