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Akkus E, Karaoğlan BB, Kayaalp M, Turmuş U, Akyol C, Utkan G. Stage-specific characterization of "early-onset colorectal cancer": Localized and synchronous metastatic disease. Int J Cancer 2025; 156:2340-2351. [PMID: 39887374 PMCID: PMC12008821 DOI: 10.1002/ijc.35336] [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: 09/23/2024] [Revised: 12/18/2024] [Accepted: 01/02/2025] [Indexed: 02/01/2025]
Abstract
Early-onset colorectal cancer (EOCRC) is an alarming entity worldwide. Yet, stage-specific characteristics and prognosis in localized and synchronous metastatic EOCRC are not well-defined. Two cohorts of CRC patients (localized and synchronous metastatic) were evaluated, defining EOCRC as the diagnosis <50 years old. Five hundred sixty-eight patients were included (n = 432 localized, 14.4% [n = 62] EOCRC and n = 136 synchronous metastatic, 20.6% [n = 28] EOCRC). 93.5% of localized and 96.5% of synchronous metastatic EOCRC patients were symptomatic at diagnosis. Among localized patients, female gender (58.1% vs. 40%, p = .008), perineural invasion (41.9% vs. 24.9%, p = .005), folinic acid, 5-fluorouracil, and oxaliplatin chemotherapy (45.2% vs. 25.2%, p = .003), and perioperative chemotherapy cycles (9.21 [± 3.10] vs. 7.98 [± 2.92], p = .006) were higher in EOCRC compared with ≥50-year. Median recurrence-free survival (RFS) and overall survival were not reached in either group (p = .234 and p = .831). Only RAS mutant status was associated with RFS (Hazard ratio: 7.09 [95% confidence interval (CI): 1.87-26.76], p < .001) in EOCRC. Among synchronous metastatic patients, urgent surgery (32.1% vs. 11.1%, p = .014) and local treatments (39.3% vs. 20.4%, p = .037) were more frequent in EOCRC. Median progression-free survival and overall survival in the EOCRC and ≥50 years were 8.07 months (95% CI: 5.03-12.97) vs. 10.03 months (95% CI, 8.40-13.10) (p = .450) and 18.57 months (95% CI, 13.33-43.03) vs. 19.83 months (95% CI, 16.07-27.30) (p = .833), respectively. Synchronous metastatic EOCRC more frequently underwent urgent surgery (32.1% vs. 8%, p = .008) and had RAS mutation (43.5% vs. 16.7%, p = .032) than localized EOCRC. This study suggests that localized and synchronous metastatic EOCRC patients may have different characteristics than average onset, without survival differences. Implementation of stage-specific characteristics into daily practice is necessary for decision-making processes in these young patients.
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Affiliation(s)
- Erman Akkus
- Department of Medical OncologyAnkara University Faculty of MedicineAnkaraTürkiye
- Ankara University Cancer Research InstituteAnkaraTürkiye
| | - Beliz Bahar Karaoğlan
- Department of Medical OncologyAnkara University Faculty of MedicineAnkaraTürkiye
- Ankara University Cancer Research InstituteAnkaraTürkiye
| | - Mehmet Kayaalp
- Department of Medical OncologyAnkara University Faculty of MedicineAnkaraTürkiye
- Ankara University Cancer Research InstituteAnkaraTürkiye
| | - Utkucan Turmuş
- Department of Internal MedicineAnkara University Faculty of MedicineAnkaraTürkiye
| | - Cihangir Akyol
- Department of SurgeryAnkara University Faculty of MedicineAnkaraTürkiye
| | - Güngör Utkan
- Department of Medical OncologyAnkara University Faculty of MedicineAnkaraTürkiye
- Ankara University Cancer Research InstituteAnkaraTürkiye
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Ameya KP, Ashikha Shirin Usman PP, Sekar D. Navigating the tumor landscape: VEGF, MicroRNAs, and the future of cancer treatment. BIOCHIMICA ET BIOPHYSICA ACTA. GENE REGULATORY MECHANISMS 2025; 1868:195091. [PMID: 40324653 DOI: 10.1016/j.bbagrm.2025.195091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/10/2025] [Accepted: 04/30/2025] [Indexed: 05/07/2025]
Abstract
Cancer progression is a multifaceted process influenced by complex interactions within the tumor microenvironment (TME). Central to these dynamics are Vascular Endothelial Growth Factor (VEGF) signalling and microRNA (miRNA) modulation, both of which play critical roles in tumor growth and angiogenesis. VEGF is essential for promoting blood vessel formation; however, its splice variant, VEGF165b, acts as an anti-angiogenic factor, presenting a paradox challenging conventional cancer therapies. Meanwhile, miRNAs regulate gene expression that significantly impacts tumor behaviour by targeting various mRNAs involved in signalling pathways. The interplay between VEGF and miRNAs opens new avenues for targeted therapies designed to disrupt the networks supporting tumor growth. Additionally, the concept of exploiting the unique properties of VEGF splice variants is being explored to develop novel treatments that enhance anti-angiogenic effects while minimizing side effects. Understanding this is crucial for advancing personalized therapies that can effectively address the challenges posed by tumor adaptability and resistance mechanisms.
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Affiliation(s)
- K P Ameya
- RNA Biology Lab, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Science (SIMATS), Saveetha University, Chennai 600077, India
| | - P P Ashikha Shirin Usman
- RNA Biology Lab, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Science (SIMATS), Saveetha University, Chennai 600077, India
| | - Durairaj Sekar
- RNA Biology Lab, Saveetha Dental College and Hospital, Saveetha Institute of Medical and Technical Science (SIMATS), Saveetha University, Chennai 600077, India.
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Kavgaci G, Akiva I, Ozon YH, Berkil H, Karadayi H, Dizdar O, Yalcin S. Evaluation of KRAS and NRAS mutations in metastatic colorectal cancer: an 8-year study of 10 754 patients in Turkey. Mol Oncol 2025. [PMID: 40411151 DOI: 10.1002/1878-0261.70042] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2025] [Revised: 03/23/2025] [Accepted: 04/15/2025] [Indexed: 05/26/2025] Open
Abstract
This study aimed to evaluate KRAS and NRAS mutations over an eight-year period to provide a comprehensive understanding of the genetic landscape of metastatic colorectal cancer (mCRC) in Turkish patients. Tumor tissue samples were collected from 10 754 patients with mCRC between January 2015 and June 2023 from multiple centers across Turkey, and all genetic analyses were performed at a single facility. DNA was analyzed for mutations in codons 12, 13, 59, 61, 117, and 146 of the KRAS and NRAS genes using nested PCR and multiplex minisequencing techniques. Among the conclusive results from 10 681 patients, 46.6% (4982) had KRAS mutations, and 53.4% (5699) were wild-type. The most common KRAS mutations were G12D (30.3%), G12V (20.1%), G13D (18.4%), and G12C (7.0%). Results from the 5699 KRAS wild-type patients revealed that 480 (8.5%) had NRAS mutations, while 91.5% were NRAS wild-type. The most frequent NRAS mutations were Q61K (19.7%), G12D (19.1%), and G12V (12%). This study provides a large-scale, real-world dataset of KRAS and NRAS mutation profiles in Turkish mCRC patients, contributing significantly to the understanding of the genetic characteristics of mCRC in this population.
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Affiliation(s)
- Gozde Kavgaci
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Izzet Akiva
- Heliks R&D and Biotechnology Inc., Istanbul, Turkey
| | | | - Hakan Berkil
- Genetiks Genetic Diagnostic Center, Istanbul, Turkey
| | | | - Omer Dizdar
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, Turkey
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González NS, Marchese PV, Baraibar I, Ros J, Salvà F, Rodríguez M, Salvà C, Vaghi C, Alcaraz A, García A, Tabernero J, Élez E. Epidermal growth factor receptor antagonists in colorectal cancer: emerging strategies for precision therapy. Expert Opin Investig Drugs 2024; 33:613-625. [PMID: 38775361 DOI: 10.1080/13543784.2024.2349287] [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: 02/23/2024] [Accepted: 04/25/2024] [Indexed: 06/25/2024]
Abstract
INTRODUCTION The global prevalence of colorectal cancer highlights the need to enhance treatment strategies for improved patient outcomes. The pivotal role of epidermal growth factor receptor (EGFR) signaling in regulating cellular processes for this disease pinpoints its value as a therapeutic target, despite the emergence of resistance mechanisms over time. AREAS COVERED This review discusses the clinical evidence supporting the use of EGFR inhibitors in molecularly-selected patients based on molecular characteristics (notably BRAF V600E and KRAS G12C) including combination approaches targeting different points in in the signaling pathway, as well as strategies such as EGFR inhibitor rechallenge. The role of HER2 inhibitors and emerging approaches such as bispecific antibodies are also reviewed. EXPERT OPINION Recently, inhibitors targeting the KRAS G12C variant have emerged, albeit with modest monotherapy activity compared to other tumor types, emphasizing the influence of histologic origins on the EGFR signaling pathway. Integration of EGFR inhibitors into precision medicine has facilitated tailored therapies addressing resistance mechanisms. Patient selection for EGFR inhibitor rechallenge guided by ctDNA findings is crucial, with ongoing investigations exploring novel combinations to enhance EGFR blockade, highlighting the transformative potential of precision medicine in shaping the future of mCRC treatment toward personalized and targeted approaches.
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Affiliation(s)
- Nadia Saoudi González
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | | | - Iosune Baraibar
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Javier Ros
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Francesc Salvà
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Marta Rodríguez
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Clara Salvà
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Caterina Vaghi
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Hematology, Oncology, and Molecular Medicine, Grande Ospedale Metropolitano Niguarda, Milan, Italy
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy
| | - Adriana Alcaraz
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Ariadna García
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
| | - Elena Élez
- Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Vall d'Hebron Hospital Campus, Barcelona, Spain
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Wu Z, Bonneil É, Belford M, Boeser C, Dunyach JJ, Thibault P. Targeted Mass Spectrometry Analyses of Somatic Mutations in Colorectal Cancer Specimens Using Differential Ion Mobility. J Proteome Res 2024; 23:644-652. [PMID: 38153093 DOI: 10.1021/acs.jproteome.3c00444] [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] [Indexed: 12/29/2023]
Abstract
Identification of K-Ras and B-Raf mutations in colorectal cancer (CRC) is essential to predict patients' response to anti-EGFR therapy and formulate appropriate therapeutic strategies to improve prognosis and survival. Here, we combined parallel reaction monitoring (PRM) with high-field asymmetric waveform ion mobility (FAIMS) to enhance mass spectrometry sensitivity and improve the identification of low-abundance K-Ras and B-Raf mutations in biological samples without immunoaffinity enrichment. In targeted LC-MS/MS analyses, FAIMS reduced the occurrence of interfering ions and enhanced precursor ion purity, resulting in a 3-fold improvement in the detection limit for K-Ras and B-Raf mutated peptides. In addition, the ion mobility separation of isomeric peptides using FAIMS facilitated the unambiguous identification of K-Ras G12D and G13D peptides. The application of targeted LC-MS/MS analyses using FAIMS is demonstrated for the detection and quantitation of B-Raf V600E, K-Ras G12D, G13D, and G12V in CRC cell lines and primary specimens.
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Affiliation(s)
- Zhaoguan Wu
- Institute for Research in Immunology and Cancer (IRIC) Université de Montréal, Montréal H3T 1J4, Canada
- Department of Chemistry, Université de Montréal, MIL Campus, Montréal H2 V 0B3, Canada
| | - Éric Bonneil
- Institute for Research in Immunology and Cancer (IRIC) Université de Montréal, Montréal H3T 1J4, Canada
| | - Michael Belford
- ThermoFisher Scientific, San Jose, California 95134, United States
| | - Cornelia Boeser
- ThermoFisher Scientific, San Jose, California 95134, United States
| | | | - Pierre Thibault
- Institute for Research in Immunology and Cancer (IRIC) Université de Montréal, Montréal H3T 1J4, Canada
- Department of Chemistry, Université de Montréal, MIL Campus, Montréal H2 V 0B3, Canada
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Saoudi González N, Ros J, Baraibar I, Salvà F, Rodríguez-Castells M, Alcaraz A, García A, Tabernero J, Élez E. Cetuximab as a Key Partner in Personalized Targeted Therapy for Metastatic Colorectal Cancer. Cancers (Basel) 2024; 16:412. [PMID: 38254903 PMCID: PMC10814823 DOI: 10.3390/cancers16020412] [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: 12/12/2023] [Revised: 01/10/2024] [Accepted: 01/16/2024] [Indexed: 01/24/2024] Open
Abstract
Cetuximab, a chimeric IgG1 monoclonal antibody targeting the epidermal growth factor receptor (EGFR), has revolutionized personalized treatment of metastatic colorectal cancer (mCRC) patients. This review highlights the mechanism of action, characteristics, and optimal indications for cetuximab in mCRC. Cetuximab has emerged as a pivotal partner for novel therapies in specific molecular subgroups, including BRAF V600E, KRAS G12C, and HER2-altered mCRC. Combining cetuximab with immunotherapy and other targeted agents further expands the therapeutic landscape, offering renewed hope for mCRC patients who face the development of resistance to conventional therapies. Ongoing clinical trials have continued to uncover innovative cetuximab-based treatment strategies, promising a brighter future for mCRC patients. This review provides a comprehensive overview of cetuximab's role and its evolving importance in personalized targeted therapy of mCRC patients, offering valuable insights into the evolving landscape of colorectal cancer treatment.
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Affiliation(s)
- Nadia Saoudi González
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Javier Ros
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Iosune Baraibar
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Francesc Salvà
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Marta Rodríguez-Castells
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Adriana Alcaraz
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Ariadna García
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
| | - Josep Tabernero
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
| | - Elena Élez
- Vall d’Hebron Institute of Oncology (VHIO), 08035 Barcelona, Spain; (N.S.G.); (F.S.)
- Vall d’Hebron Hospital Campus, 08035 Barcelona, Spain
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Mu M, Zhang Q, Zhao C, Li X, Chen Z, Sun X, Yu J. 3-Bromopyruvate overcomes cetuximab resistance in human colorectal cancer cells by inducing autophagy-dependent ferroptosis. Cancer Gene Ther 2023; 30:1414-1425. [PMID: 37558749 PMCID: PMC10581902 DOI: 10.1038/s41417-023-00648-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 06/15/2023] [Accepted: 07/12/2023] [Indexed: 08/11/2023]
Abstract
Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide. Cetuximab, in combination with chemotherapy, is effective for treating patients with wild-type KRAS/BRAF metastatic CRC (mCRC). However, intrinsic or acquired drug resistance often limits the use of cetuximab. In this study, we investigated the potential of co-treatment with 3-Bromopyruvate (3-BP) and cetuximab to overcome cetuximab resistance in CRC, both in vitro and in vivo. Our results demonstrated that the co-treatment of 3-BP and cetuximab synergistically induced an antiproliferative effect in both CRC cell lines with intrinsic cetuximab resistance (DLD-1 (KRASG13D/-) and HT29 (BRAFV600E)) and in a cetuximab-resistant cell line derived from Caco-2 with acquired resistance (Caco-2-CR). Further analysis revealed that co-treatment induced ferroptosis, autophagy, and apoptosis. Mechanistically, co-treatment inhibited FOXO3a phosphorylation and degradation and activated the FOXO3a/AMPKα/pBeclin1 and FOXO3a/PUMA pathways, leading to the promotion of ferroptosis, autophagy, and apoptosis in DLD-1 (KRASG13D/-), HT29 (BRAFV600E), and Caco-2-CR cells. In conclusion, our findings suggest that co-treatment with 3-BP and cetuximab could be a promising strategy to overcome cetuximab resistance in human CRC.
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Affiliation(s)
- Mingchao Mu
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China
| | - Qin Zhang
- Department of Dermatology, Northwest Hospital, the Second Affiliated Hospital of Xi'an Jiaotong University, 710004, Xi'an, Shaanxi, China
| | - Chenye Zhao
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China
| | - Xiaopeng Li
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China
| | - Zilu Chen
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China
| | - Xuejun Sun
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China.
| | - Junhui Yu
- Department of General Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, 710061, Xi'an, Shaanxi, China.
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Saoudi González N, Salvà F, Ros J, Baraibar I, Rodríguez-Castells M, García A, Alcaráz A, Vega S, Bueno S, Tabernero J, Elez E. Unravelling the Complexity of Colorectal Cancer: Heterogeneity, Clonal Evolution, and Clinical Implications. Cancers (Basel) 2023; 15:4020. [PMID: 37627048 PMCID: PMC10452468 DOI: 10.3390/cancers15164020] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2023] [Revised: 08/01/2023] [Accepted: 08/02/2023] [Indexed: 08/27/2023] Open
Abstract
Colorectal cancer (CRC) is a global health concern and a leading cause of death worldwide. The disease's course and response to treatment are significantly influenced by its heterogeneity, both within a single lesion and between primary and metastatic sites. Biomarkers, such as mutations in KRAS, NRAS, and BRAF, provide valuable guidance for treatment decisions in patients with metastatic CRC. While high concordance exists between mutational status in primary and metastatic lesions, some heterogeneity may be present. Circulating tumor DNA (ctDNA) analysis has proven invaluable in identifying genetic heterogeneity and predicting prognosis in RAS-mutated metastatic CRC patients. Tumor heterogeneity can arise from genetic and non-genetic factors, affecting tumor development and response to therapy. To comprehend and address clonal evolution and intratumoral heterogeneity, comprehensive genomic studies employing techniques such as next-generation sequencing and computational analysis are essential. Liquid biopsy, notably through analysis of ctDNA, enables real-time clonal evolution and treatment response monitoring. However, challenges remain in standardizing procedures and accurately characterizing tumor subpopulations. Various models elucidate the origin of CRC heterogeneity, highlighting the intricate molecular pathways involved. This review focuses on intrapatient cancer heterogeneity and genetic clonal evolution in metastatic CRC, with an emphasis on clinical applications.
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Affiliation(s)
- Nadia Saoudi González
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Francesc Salvà
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Javier Ros
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Iosune Baraibar
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Marta Rodríguez-Castells
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Ariadna García
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
| | - Adriana Alcaráz
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Sharela Vega
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Sergio Bueno
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Josep Tabernero
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
| | - Elena Elez
- Vall d’Hebron Institute of Oncology, 08035 Barcelona, Spain; (N.S.G.)
- Oncology Department, Vall d’Hebron Hospital, 08035 Barcelona, Spain
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Ray SK, Mukherjee S. Starring Role of Biomarkers and Anticancer Agents as a Major Driver in Precision Medicine of Cancer Therapy. Curr Mol Med 2023; 23:111-126. [PMID: 34939542 DOI: 10.2174/1566524022666211221152947] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 10/18/2021] [Accepted: 10/26/2021] [Indexed: 12/16/2022]
Abstract
Precision medicine is the most modern contemporary medicine approach today, based on great amount of data on people's health, individual characteristics, and life circumstances, and employs the most effective ways to prevent and cure diseases. Precision medicine in cancer is the most precise and viable treatment for every cancer patient based on the disease's genetic profile. Precision medicine changes the standard one size fits all medication model, which focuses on average responses to care. Consolidating modern methodologies for streamlining and checking anticancer drugs can have long-term effects on understanding the results. Precision medicine can help explicit anticancer treatments using various drugs and even in discovery, thus becoming the paradigm of future cancer medicine. Cancer biomarkers are significant in precision medicine, and findings of different biomarkers make this field more promising and challenging. Naturally, genetic instability and the collection of extra changes in malignant growth cells are ways cancer cells adapt and survive in a hostile environment, for example, one made by these treatment modalities. Precision medicine centers on recognizing the best treatment for individual patients, dependent on their malignant growth and genetic characterization. This new era of genomics progressively referred to as precision medicine, has ignited a new episode in the relationship between genomics and anticancer drug development.
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Affiliation(s)
| | - Sukhes Mukherjee
- Department of Biochemistry. All India Institute of Medical Sciences. Bhopal, Madhya Pradesh-462020. India
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Burska AN, Ilyassova B, Dildabek A, Khamijan M, Begimbetova D, Molnár F, Sarbassov DD. Enhancing an Oxidative "Trojan Horse" Action of Vitamin C with Arsenic Trioxide for Effective Suppression of KRAS-Mutant Cancers: A Promising Path at the Bedside. Cells 2022; 11:3454. [PMID: 36359850 PMCID: PMC9657932 DOI: 10.3390/cells11213454] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/19/2022] [Accepted: 10/24/2022] [Indexed: 11/06/2022] Open
Abstract
The turn-on mutations of the KRAS gene, coding a small GTPase coupling growth factor signaling, are contributing to nearly 25% of all human cancers, leading to highly malignant tumors with poor outcomes. Targeting of oncogenic KRAS remains a most challenging task in oncology. Recently, the specific G12C mutant KRAS inhibitors have been developed but with a limited clinical outcome because they acquire drug resistance. Alternatively, exploiting a metabolic breach of KRAS-mutant cancer cells related to a glucose-dependent sensitivity to oxidative stress is becoming a promising indirect cancer targeting approach. Here, we discuss the use of a vitamin C (VC) acting in high dose as an oxidative "Trojan horse" agent for KRAS-mutant cancer cells that can be potentiated with another oxidizing drug arsenic trioxide (ATO) to obtain a potent and selective cytotoxic impact. Moreover, we outline the advantages of VC's non-natural enantiomer, D-VC, because of its distinctive pharmacokinetics and lower toxicity. Thus, the D-VC and ATO combination shows a promising path to treat KRAS-mutant cancers in clinical settings.
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Affiliation(s)
- Agata N. Burska
- Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan
| | | | - Aruzhan Dildabek
- Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan
| | - Medina Khamijan
- Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan
| | - Dinara Begimbetova
- National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan
| | - Ferdinand Molnár
- Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan
| | - Dos D. Sarbassov
- Department of Biology, Nazarbayev University, Astana 010000, Kazakhstan
- National Laboratory Astana, Nazarbayev University, Astana 010000, Kazakhstan
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Damato A, Rotolo M, Caputo F, Borghi E, Iachetta F, Pinto C. New Potential Immune Biomarkers in the Era of Precision Medicine: Lights and Shadows in Colorectal Cancer. Life (Basel) 2022; 12:1137. [PMID: 36013315 PMCID: PMC9410155 DOI: 10.3390/life12081137] [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: 07/02/2022] [Revised: 07/21/2022] [Accepted: 07/26/2022] [Indexed: 11/16/2022] Open
Abstract
Genetic alterations in CRC have shown a negative predictive and prognostic role in specific target therapies. The onset of immunotherapy has also undergone remarkable therapeutic innovation, although limited to a small subgroup of patients, the MSI-H/dMMR, which represents only 5% of CRC. Research is moving forward to identify whether other biomarkers can predict response to ICIs, despite various limitations regarding expression and identification methods. For this purpose, TMB, LAG3, and PD-L1 expression have been retrospectively evaluated in several solid tumors establishing the rationale to design clinical trials with concurrent inhibition of LAG3 and PD-1 results in a significant advantage in PFS and OS in advanced melanoma patients. Based on these data, there are clinical trials ongoing in the CRC as well. This review aims to highlight what is already known about genetic mutations and genomic alterations in CRC, their inhibition with targeted therapies and immune checkpoints inhibitors, and new findings useful to future treatment strategies.
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Affiliation(s)
- Angela Damato
- Medical Oncology, Comprehensive Cancer Center, Azienda USL-IRCCS Reggio Emilia, 42122 Reggio Emilia, Italy; (M.R.); (F.C.); (E.B.); (F.I.); (C.P.)
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12
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Crisafulli G, Sartore-Bianchi A, Lazzari L, Pietrantonio F, Amatu A, Macagno M, Barault L, Cassingena A, Bartolini A, Luraghi P, Mauri G, Battuello P, Personeni N, Zampino MG, Pessei V, Vitiello PP, Tosi F, Idotta L, Morano F, Valtorta E, Bonoldi E, Germano G, Di Nicolantonio F, Marsoni S, Siena S, Bardelli A. Temozolomide Treatment Alters Mismatch Repair and Boosts Mutational Burden in Tumor and Blood of Colorectal Cancer Patients. Cancer Discov 2022; 12:1656-1675. [PMID: 35522273 PMCID: PMC9394384 DOI: 10.1158/2159-8290.cd-21-1434] [Citation(s) in RCA: 73] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2021] [Revised: 04/16/2022] [Accepted: 05/04/2022] [Indexed: 01/07/2023]
Abstract
The majority of metastatic colorectal cancers (mCRC) are mismatch repair (MMR) proficient and unresponsive to immunotherapy, whereas MMR-deficient (MMRd) tumors often respond to immune-checkpoint blockade. We previously reported that the treatment of colorectal cancer preclinical models with temozolomide (TMZ) leads to MMR deficiency, increased tumor mutational burden (TMB), and sensitization to immunotherapy. To clinically translate these findings, we designed the ARETHUSA clinical trial whereby O6-methylguanine-DNA-methyltransferase (MGMT)-deficient, MMR-proficient, RAS-mutant mCRC patients received priming therapy with TMZ. Analysis of tissue biopsies and circulating tumor DNA (ctDNA) revealed the emergence of a distinct mutational signature and increased TMB after TMZ treatment. Multiple alterations in the nucleotide context favored by the TMZ signature emerged in MMR genes, and the p.T1219I MSH6 variant was detected in ctDNA and tissue of 94% (16/17) of the cases. A subset of patients whose tumors displayed the MSH6 mutation, the TMZ mutational signature, and increased TMB achieved disease stabilization upon pembrolizumab treatment. SIGNIFICANCE MMR-proficient mCRCs are unresponsive to immunotherapy. We provide the proof of concept that inactivation of MMR genes can be achieved pharmacologically with TMZ and molecularly monitored in the tissue and blood of patients with mCRC. This strategy deserves additional evaluation in mCRC patients whose tumors are no longer responsive to standard-of-care treatments. See related commentary by Willis and Overman, p. 1612. This article is highlighted in the In This Issue feature, p. 1599.
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Affiliation(s)
- Giovanni Crisafulli
- Department of Oncology, University of Torino, Candiolo, Italy.,Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy
| | - Andrea Sartore-Bianchi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.,Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Luca Lazzari
- The FIRC Institute of Molecular Oncology, Milan, Italy
| | - Filippo Pietrantonio
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Alessio Amatu
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Marco Macagno
- Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy
| | - Ludovic Barault
- Department of Oncology, University of Torino, Candiolo, Italy.,Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy
| | - Andrea Cassingena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | | | - Paolo Luraghi
- The FIRC Institute of Molecular Oncology, Milan, Italy
| | - Gianluca Mauri
- Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy.,The FIRC Institute of Molecular Oncology, Milan, Italy
| | - Paolo Battuello
- Department of Oncology, University of Torino, Candiolo, Italy
| | - Nicola Personeni
- Department of Biomedical Sciences, Humanitas University, Pieve Emanuele, Milan, Italy.,Medical Oncology and Hematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy
| | - Maria Giulia Zampino
- Division of Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology, IRCCS, Milan, Italy
| | | | - Pietro Paolo Vitiello
- Department of Oncology, University of Torino, Candiolo, Italy.,Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy
| | - Federica Tosi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Laura Idotta
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Federica Morano
- Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Emanuele Valtorta
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Emanuela Bonoldi
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy
| | - Giovanni Germano
- Department of Oncology, University of Torino, Candiolo, Italy.,Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy
| | - Federica Di Nicolantonio
- Department of Oncology, University of Torino, Candiolo, Italy.,Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy
| | | | - Salvatore Siena
- Niguarda Cancer Center, Grande Ospedale Metropolitano Niguarda, Milan, Italy.,Department of Oncology and Hemato-Oncology, Università degli Studi di Milano, Milan, Italy
| | - Alberto Bardelli
- Department of Oncology, University of Torino, Candiolo, Italy.,Candiolo Cancer Institute, FPO - IRCCS, Candiolo, Italy.,Corresponding Author: Alberto Bardelli, University of Turin, Department of Oncology, Candiolo Cancer Institute, FPO - IRCCS, Str.Prov.le 142, km 3.95, 10060, Candiolo, Torino, Italy. Phone/Fax: 39-011-993-3235; E-mail:
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Gong RH, Chen M, Huang C, Wong HLX, Kwan HY, Bian Z. Combination of artesunate and WNT974 induces KRAS protein degradation by upregulating E3 ligase ANACP2 and β-TrCP in the ubiquitin–proteasome pathway. Cell Commun Signal 2022; 20:34. [PMID: 35305671 PMCID: PMC8934478 DOI: 10.1186/s12964-022-00834-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Accepted: 01/29/2022] [Indexed: 12/01/2022] Open
Abstract
Background KRAS mutation is one of the dominant gene mutations in colorectal cancer (CRC). Up to present, targeting KRAS for CRC treatment remains a clinical challenge. WNT974 (LGK974) is a porcupine inhibitor that interferes Wnt signaling pathway. Artesunate (ART) is a water-soluble semi-synthetic derivative of artemisinin. Methods The synergistic effect of ART and WNT974 combination in reducing CRC cell viability was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. RT-PCR was utilized for the mRNA levels of KRAS, CUL7, ANAPC2, UBE2M, RNF123, SYVN1, or β-TrCP. Western blot assay was utilized for the protein levels of NRAS, HRAS, KRAS, ANAPC2, β-TrCP, GSK-3β, p-Akt (Ser473), t-Akt, p-PI3K (Tyr458), t-PI3K, p-mTOR (Ser2448), t-mTOR. Xenograft mouse model assay was performed for the anti-CRC effect of combination of ART and WNT974 in vivo. IHC assay was utilized for the levels of KRAS, β-TrCP, GSK-3β or ANAPC2 in tumor tissues. Results Our study shows that the combination of WNT974 and ART exhibits synergistic effect in reducing CRC growth. The combination treatment significantly reduces KRAS protein level and activity in CRC cells. Interestingly, the combination treatment increases E3 ligases ANAPC2 expression. Our data show that overexpression of ANAPC2 significantly reduces KRAS protein levels, which is reversed by MG132. Knockdown of ANAPC2 in CRC abolishes the combination treatment-reduce KRAS expression. Besides, the treatment also increases the expressions of GSK-3β and E3 ligase β-TrCP that is known to degrade GSK-3β-phosphorylated KRAS protein. Knockdown of β-TrCP- and inhibition of GSK-3β abolish the combination treatment-induce KRAS ubiquitination and reduction in expression. Last but not least, combination treatment suppresses PI3K/Akt/m-TOR signaling pathway. Conclusions Our data clearly show that the combination treatment significantly enhances KRAS protein degradation via the ubiquitination ubiquitin–proteasome pathway, which is also demonstrated in xenograft mouse model. The study provides strong scientific evidence for the development of the combination of WNT974 and ART as KRAS-targeting therapeutics for CRC treatment.
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Ros J, Saoudi N, Salvà F, Baraibar I, Alonso G, Tabernero J, Elez E. Ongoing and evolving clinical trials enhancing future colorectal cancer treatment strategies. Expert Opin Investig Drugs 2022; 31:235-247. [PMID: 35133234 DOI: 10.1080/13543784.2022.2040016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
INTRODUCTION Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (CRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF and MSI status and over the last few years several promising new biomarkers have also been identified. Circulating tumor DNA has reshaped the prognosis of localized CRC. These genomic findings can guide treatment management to improve clinical outcomes. AREAS COVERED Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory and metastatic CRC. In the localized stage, al clinical trials involving new approaches such as liquid biopsy or neoadjuvant immunotherapy are also discussed. Molecular alterations and targeted agents are described, and data from completed and ongoing studies with targeted therapy and immunotherapies are presented. EXPERT OPINION The implementation of liquid biopsies in the localized CRC setting has reshaped management of this disease. The expanded use of biomarkers to guide the treatment of patients with CRC has revealed a level of complexity arising from interactions between different biomarkers. Prevalence of most established targetable biomarkers is low, however the number of identified biomarkers in CRC is increasing. Thus, metastatic CRC may ultimately be considered an umbrella diagnosis encompassing numerous rare disease subtypes.
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Affiliation(s)
- Javier Ros
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain.,Department of Precision Medicine, Medical Oncology, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Campania, Italy
| | - Nadia Saoudi
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Francesc Salvà
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Iosune Baraibar
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Guzman Alonso
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Elena Elez
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Promsorn J, Chadbunchachai P, Somsap K, Paonariang K, Sa-ngaimwibool P, Apivatanasiri C, Lahoud RM, Harisinghani M. Imaging features associated with survival outcomes among colorectal cancer patients with and without KRAS mutation. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2021. [DOI: 10.1186/s43055-020-00393-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Abstract
Background
Mutations in Kirsten rat sarcoma proto-oncogene (KRAS) have been shown to be associated with advanced-stage colorectal cancer (CRC), negative disease outcomes, and poor response to treatment. The purpose of this study was to investigate which CT features are biomarkers for KRAS gene mutation and impact the survival outcomes of colorectal cancer patients.
Results
Of the 113 CRC patients included in the study, 46 had KRAS mutations (40.71%) and 67 had no mutations (59.29%). Regional lymph node necrosis was the only imaging feature significantly associated with KRAS mutation (P = 0.011). Higher T staging and liver, lung, and distant metastasis were prognostic factors for CRC (P = 0.014, P < 0.001, P = 0.022, P < 0.001, respectively). There were no significant differences in overall survival between patients with KRAS mutations and those without (P = 0.159). However, in patients with no KRAS mutation, those with CRC on the left side had a significantly higher rate of survival than those with CRC on the right (P = 0.005).
Conclusion
Regional lymph node necrosis may be an imaging biomarker of CRC with KRAS mutation, possibly indicating poor prognosis.
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Hu LF, Lan HR, Huang D, Li XM, Jin KT. Personalized Immunotherapy in Colorectal Cancers: Where Do We Stand? Front Oncol 2021; 11:769305. [PMID: 34888246 PMCID: PMC8649954 DOI: 10.3389/fonc.2021.769305] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Accepted: 10/26/2021] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer death in the world. Immunotherapy using monoclonal antibodies, immune-checkpoint inhibitors, adoptive cell therapy, and cancer vaccines has raised great hopes for treating poor prognosis metastatic CRCs that are resistant to the conventional therapies. However, high inter-tumor and intra-tumor heterogeneity hinder the success of immunotherapy in CRC. Patients with a similar tumor phenotype respond differently to the same immunotherapy regimen. Mutation-based classification, molecular subtyping, and immunoscoring of CRCs facilitated the multi-aspect grouping of CRC patients and improved immunotherapy. Personalized immunotherapy using tumor-specific neoantigens provides the opportunity to consider each patient as an independent group deserving of individualized immunotherapy. In the recent decade, the development of sequencing and multi-omics techniques has helped us classify patients more precisely. The expansion of such advanced techniques along with the neoantigen-based immunotherapy could herald a new era in treating heterogeneous tumors such as CRC. In this review article, we provided the latest findings in immunotherapy of CRC. We elaborated on the heterogeneity of CRC patients as a bottleneck of CRC immunotherapy and reviewed the latest advances in personalized immunotherapy to overcome CRC heterogeneity.
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Affiliation(s)
- Li-Feng Hu
- Department of Colorectal Surgery, Shaoxing People’s Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, China
| | - Huan-Rong Lan
- Department of Breast and Thyroid Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Dong Huang
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Xue-Min Li
- Department of Hepatobiliary Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
| | - Ke-Tao Jin
- Department of Colorectal Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China
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Ros J, Baraibar I, Martini G, Salvà F, Saoudi N, Cuadra-Urteaga JL, Dienstmann R, Tabernero J, Élez E. The Evolving Role of Consensus Molecular Subtypes: a Step Beyond Inpatient Selection for Treatment of Colorectal Cancer. Curr Treat Options Oncol 2021; 22:113. [PMID: 34741675 DOI: 10.1007/s11864-021-00913-5] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/03/2021] [Indexed: 12/24/2022]
Abstract
OPINION STATEMENT The heterogenous nature of colorectal cancer (CRC) renders it a major clinical challenge. Increasing genomic understanding of CRC has improved our knowledge of this heterogeneity and the main cancer drivers, with significant improvements in clinical outcomes. Comprehensive molecular characterization has allowed clinicians a more precise range of treatment options based on biomarker selection. Furthermore, this deep molecular understanding likely extends therapeutic options to a larger number of patients. The biological associations of consensus molecular subtypes (CMS) with clinical outcomes in localized CRC have been validated in retrospective clinical trials. The prognostic role of CMS has also been confirmed in the metastatic setting, with CMS2 having the best prognosis, whereas CMS1 tumors are associated with a higher risk of progression and death after chemotherapy. Similarly, according to mesenchymal features and immunosuppressive molecules, CMS1 responds to immunotherapy, whereas CMS4 has a poorer prognosis, suggesting that a CMS1 signature could identify patients who may benefit from immune checkpoint inhibitors regardless of microsatellite instability (MSI) status. The main goal of these comprehensive analyses is to switch from "one marker-one drug" to "multi-marker drug combinations" allowing oncologists to give "the right drug to the right patient." Despite the revealing data from transcriptomic analyses, the high rate of intra-tumoral heterogeneity across the different CMS subgroups limits its incorporation as a predictive biomarker. In clinical practice, when feasible, comprehensive genomic tests should be performed to identify potentially targetable alterations, particularly in RAS/BRAF wild-type, MSI, and right-sided tumors. Furthermore, CMS has not only been associated with clinical outcomes and specific tumor and patient phenotypes but also with specific microbiome patterns. Future steps will include the integration of clinical features, genomics, transcriptomics, and microbiota to select the most accurate biomarkers to identify optimal treatments, improving individual clinical outcomes. In summary, CMS is context specific, identifies a level of heterogeneity beyond standard genomic biomarkers, and offers a means of maximizing personalized therapy.
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Affiliation(s)
- Javier Ros
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain. .,Department of Precision Medicine, Medical Oncology, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Campania, Italy.
| | - Iosune Baraibar
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Giulia Martini
- Department of Precision Medicine, Medical Oncology, Università Degli Studi Della Campania Luigi Vanvitelli, Naples, Campania, Italy
| | - Francesc Salvà
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Nadia Saoudi
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | | | - Rodrigo Dienstmann
- Oncology Data Science (ODysSey) Group, Vall D'Hebron Institute of Oncology (VHIO), Hospital Universitari Vall D'Hebron, Vall D'Hebron Barcelona Hospital Campus (Spain), Barcelona, Spain
| | - Josep Tabernero
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain.,IOB, Barcelona, Spain.,UVic-UCC, Vic, Spain
| | - Elena Élez
- Medical Oncology, Vall d'Hebron University Hospital and Vall D'Hebron Institute of Oncology (VHIO), Barcelona, Spain
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Osei-Bordom DC, Kamarajah S, Christou N. Colorectal Cancer, Liver Metastases and Biotherapies. Biomedicines 2021; 9:894. [PMID: 34440099 PMCID: PMC8389538 DOI: 10.3390/biomedicines9080894] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2021] [Revised: 07/13/2021] [Accepted: 07/21/2021] [Indexed: 12/01/2022] Open
Abstract
(1) Background: colorectal cancer (CRC) is one of the deadliest causes of death by cancer worldwide. Its first main metastatic diffusion spreads to the liver. Different mechanisms such as the epithelial-mesenchymal transition and angiogenesis are the characteristics of this invasion. At this stage, different options are possible and still in debate, especially regarding the use of targeted therapeutics and biotherapies. (2) Methods: A review of the literature has been done focusing on the clinical management of liver metastasis of colorectal cancer and the contribution of biotherapies in this field. (3) Results: In a clinical setting, surgeons and oncologists consider liver metastasis in CRC into two groups to launch adapted therapeutics: resectable and non-resectable. Around these two entities, the combination of targeted therapies and biotherapies are of high interest and are currently tested to know in which molecular and clinical conditions they have to be applied to impact positively both on survival and quality of life of patients.
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Affiliation(s)
- Daniel-Clement Osei-Bordom
- Department of General Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, UK; (D.-C.O.-B.); (S.K.)
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TT, UK
- NIHR Birmingham Biomedical Research Centre, Centre for Liver and Gastroenterology Research, University of Birmingham, Birmingham B15 2TT, UK
| | - Sivesh Kamarajah
- Department of General Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, UK; (D.-C.O.-B.); (S.K.)
| | - Niki Christou
- Department of General Surgery, Queen Elizabeth Hospital, University Hospitals Birmingham, Birmingham B15 2TH, UK; (D.-C.O.-B.); (S.K.)
- Department of General Surgery, University Hospital of Limoges, 87000 Limoges, France
- EA3842 CAPTuR Laboratory “Cell Activation Control, Tumor Progression and Therapeutic Resistance”, Faculty of Medicine, 2 Rue du Docteur Marcland, 87025 Limoges, France
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Koulouris A, Tsagkaris C, Messaritakis I, Gouvas N, Sfakianaki M, Trypaki M, Spyrou V, Christodoulakis M, Athanasakis E, Xynos E, Tzardi M, Mavroudis D, Souglakos J. Resectable Colorectal Cancer: Current Perceptions on the Correlation of Recurrence Risk, Microbiota and Detection of Genetic Mutations in Liquid Biopsies. Cancers (Basel) 2021; 13:3522. [PMID: 34298740 PMCID: PMC8304269 DOI: 10.3390/cancers13143522] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2021] [Revised: 07/09/2021] [Accepted: 07/12/2021] [Indexed: 12/12/2022] Open
Abstract
Metastatic colorectal cancer (mCRC) remains a highly lethal malignancy, although considerable progress has resulted from molecular alterations in guiding optimal use of available treatments. CRC recurrence remains a great barrier in the disease management. Hence, the spotlight turns to newly mapped fields concerning recurrence risk factors in patients with resectable CRC with a focus on genetic mutations, microbiota remodeling and liquid biopsies. There is an urgent need for novel biomarkers to address disease recurrence since specific genetic signatures can identify a higher or lower recurrence risk (RR) and, thus, be used both as biomarkers and treatment targets. To a large extent, CRC is mediated by the immune and inflammatory interplay of microbiota, through intestinal dysbiosis. Clarification of these mechanisms will yield new opportunities, leading not only to the appropriate stratification policies, but also to more precise, personalized monitoring and treatment navigation. Under this perspective, early detection of post-operative CRC recurrence is of utmost importance. Ongoing trials, focusing on circulating tumor cells (CTCs) and, even more, circulating tumor DNA (ctDNA), seem to pave the way to a promising, minimally invasive but accurate and life-saving monitoring, not only supporting personalized treatment but favoring patients' quality of life, as well.
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Affiliation(s)
- Andreas Koulouris
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece; (A.K.); (M.S.); (M.T.); (D.M.); (J.S.)
- Department of Medical Oncology, University Hospital of Heraklion, 71110 Heraklion, Greece
| | | | - Ippokratis Messaritakis
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece; (A.K.); (M.S.); (M.T.); (D.M.); (J.S.)
| | - Nikolaos Gouvas
- Medical School, University of Cyprus, Nicosia 20537, Cyprus;
| | - Maria Sfakianaki
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece; (A.K.); (M.S.); (M.T.); (D.M.); (J.S.)
| | - Maria Trypaki
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece; (A.K.); (M.S.); (M.T.); (D.M.); (J.S.)
| | - Vasiliki Spyrou
- Department of Radiation Oncology, Hygeia Hospital, 15123 Athens, Greece;
| | - Manousos Christodoulakis
- Department of General Surgery, Venizeleio General Hospital, Leoforos Knossou 44, 71409 Heraklion, Greece;
| | - Elias Athanasakis
- Department of Surgery, University General Hospital of Heraklion, 71110 Heraklion, Greece;
| | - Evangelos Xynos
- Department of Surgery, Creta Interclinic Hospital of Heraklion, 71305 Heraklion, Greece;
| | - Maria Tzardi
- Laboratory of Pathology, University General Hospital of Heraklion, 70013 Heraklion, Greece;
| | - Dimitrios Mavroudis
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece; (A.K.); (M.S.); (M.T.); (D.M.); (J.S.)
- Department of Medical Oncology, University Hospital of Heraklion, 71110 Heraklion, Greece
| | - John Souglakos
- Laboratory of Translational Oncology, Medical School, University of Crete, 70013 Heraklion, Greece; (A.K.); (M.S.); (M.T.); (D.M.); (J.S.)
- Department of Medical Oncology, University Hospital of Heraklion, 71110 Heraklion, Greece
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21
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Doubleday PF, Fornelli L, Ntai I, Kelleher NL. Oncogenic KRAS creates an aspartate metabolism signature in colorectal cancer cells. FEBS J 2021; 288:6683-6699. [PMID: 34227245 DOI: 10.1111/febs.16111] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 06/25/2021] [Accepted: 07/05/2021] [Indexed: 12/27/2022]
Abstract
Oncogenic mutations in the KRAS gene are found in 30-50% of colorectal cancers (CRC), and recent findings have demonstrated independent and nonredundant roles for wild-type and mutant KRAS alleles in governing signaling and metabolism. Here, we quantify proteomic changes manifested by KRAS mutation and KRAS allele loss in isogenic cell lines. We show that the expression of KRASG13D upregulates aspartate metabolizing proteins including PCK1, PCK2, ASNS, and ASS1. Furthermore, differential expression analyses of transcript-level data from CRC tumors identified the upregulation of urea cycle enzymes in CRC. We find that expression of ASS1 supports colorectal cancer cell proliferation and promotes tumor formation in vitro. We show that loss of ASS1 can be rescued with high levels of several metabolites.
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Affiliation(s)
- Peter F Doubleday
- Department of Molecular Biosciences and Chemistry, Northwestern University, Evanston, IL, USA
| | - Luca Fornelli
- Department of Biology, Department of Biology, University of Oklahoma, Norman, OK, USA
| | | | - Neil L Kelleher
- Department of Molecular Biosciences and Chemistry, Northwestern University, Evanston, IL, USA
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22
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Huang J, Zang Q, Wen Y, Pan Z, Yao Z, Huang M, Huang J, Chen J, Wang R. Prognostic value of KRAS mutation in patients undergoing pulmonary metastasectomy for colorectal cancer: A systematic review and meta-analysis. Crit Rev Oncol Hematol 2021; 160:103308. [PMID: 33753248 DOI: 10.1016/j.critrevonc.2021.103308] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 02/26/2021] [Accepted: 03/03/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The purpose of the study was to evaluate whether KRAS mutation could be an independent prognostic biomarker in patients undergoing pulmonary metastasectomy (PM) for colorectal cancer (CRC). METHODS A systemic review was performed by searching online databases to identify studies reporting overall survival (OS) and recurrence free survival (RFS) of CRC patients undergoing PM. Pooled HRs were calculated for OS and RFS. RESULTS A total of 15233 patients from 60 studies were included. Pooled analysis showed that KRAS mutation was associated with worse OS (HR: 1.86, 95 % Cl: 1.35-2.57) and RFS (HR: 1.68, 95 % Cl: 1.38-2.04). A significant effect on OS and/or RFS was also shown by other 18 factors. CONCLUSIONS This meta-analysis found that KRAS mutation is an important prognostic predictor for OS and RFS in CRC patients undergoing PM, supporting a comprehensive model including clinicopathological and biological factors for optimal patients selection and prognosis for surgical treatment.
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Affiliation(s)
- Junfeng Huang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Nanshan School of Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Qing Zang
- State Key Laboratory of Respiratory Disease, National Clinical Research Center for Respiratory Disease, Guangzhou Institute of Respiratory Health, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China; Nanshan School of Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Yaokai Wen
- Nanshan School of Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhe Pan
- Nanshan School of Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Zhiyuan Yao
- Nanshan School of Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Mingkai Huang
- Nanshan School of Medicine, Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jiongqiang Huang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China
| | - Jingsong Chen
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
| | - Rongchang Wang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, Guangdong, China.
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23
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Siva N, Gupta S, Gupta A, Shukla JN, Malik B, Shukla N. Genome-editing approaches and applications: a brief review on CRISPR technology and its role in cancer. 3 Biotech 2021; 11:146. [PMID: 33732568 PMCID: PMC7910401 DOI: 10.1007/s13205-021-02680-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2020] [Accepted: 02/05/2021] [Indexed: 02/08/2023] Open
Abstract
The development of genome-editing technologies in 1970s has discerned a new beginning in the field of science. Out of different genome-editing approaches such as Zing-finger nucleases, TALENs, and meganucleases, clustered regularly interspaced short palindromic repeats-CRISPR-associated protein 9 (CRISPR/Cas9) is a recent and versatile technology that has the ability of making changes to the genome of different organisms with high specificity. Cancer is a complex process that is characterized by multiple genetic and epigenetic changes resulting in abnormal cell growth and proliferation. As cancer is one of the leading causes of deaths worldwide, a large number of studies are done to understand the molecular mechanisms underlying the development of cancer. Because of its high efficiency and specificity, CRISPR/Cas9 has emerged as a novel and powerful tool in the field of cancer research. CRISPR/Cas9 has the potential to accelerate cancer research by dissecting tumorigenesis process, generating animal and cellular models, and identify drug targets for chemotherapeutic approaches. However, despite having tremendous potential, there are certain challenges associated with CRISPR/Cas9 such as safe delivery to the target, potential off-target effects and its efficacy which needs to be addressed prior to its clinical application. In this review, we give a gist of different genome-editing technologies with a special focus on CRISPR/Cas9 development, its mechanism of action and its applications, especially in different type of cancers. We also highlight the importance of CRISPR/Cas9 in generating animal models of different cancers. Finally, we present an overview of the clinical trials and discuss the challenges associated with translating CRISPR/Cas9 in clinical use.
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Affiliation(s)
- Narmadhaa Siva
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Statue Circle, Jaipur, India
| | - Sonal Gupta
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Statue Circle, Jaipur, India
| | - Ayam Gupta
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Statue Circle, Jaipur, India
| | - Jayendra Nath Shukla
- Department of Biotechnology, School of Life Sciences, Central University of Rajasthan, Bandarsindari, Ajmer, India
| | - Babita Malik
- Department of Chemistry, Manipal University Jaipur, Jaipur, India
| | - Nidhi Shukla
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Statue Circle, Jaipur, India
- Department of Chemistry, Manipal University Jaipur, Jaipur, India
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24
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Nguyen HT, Le DT, Duong QH, Tatipamula VB, Van Nguyen B. High frequency of microsatellite instability and its substantial co-existence with KRAS and BRAF mutations in Vietnamese patients with colorectal cancer. Oncol Lett 2020; 21:41. [PMID: 33262833 PMCID: PMC7693389 DOI: 10.3892/ol.2020.12302] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Accepted: 10/23/2020] [Indexed: 12/24/2022] Open
Abstract
Tumor heterogeneity and resistance to chemotherapy have been recognized as two major obstacles in the diagnosis and treatment of colorectal cancer (CRC). Microsatellite instability (MSI) and KRAS and BRAF mutations are common diagnostic factors that have been widely used to classify CRC for therapeutics. In the present study, 151 patients with CRC were analyzed from the two most populous ethnic groups of Vietnam, Kinh and Muong, for their MSI status, frequency of KRAS and BRAF mutations, and their clinical implications. MSI-high (MSI-H) was detected in 45.0% (68/151), while mutated KRAS and BRAF were identified in 37.1% (56/151) and 2.6% (4/151) of the cases, respectively. There was a substantial co-existence of MSI-H with KRAS (27/56; 48.2%) and BRAF (3/4; 75.0%) mutations. Statistical analysis showed that MSI-H tumors were significantly associated with colon location (P=0.011) and more advanced T stages (P=0.016). KRAS exon 2 mutations were significantly more likely to be detected in patients who belonged to the Muong ethnic group (P=0.013) or those with no/fewer lymph node metastasis (P=0.048) as compared with their counterparts. In summary, the data revealed typical molecular features of Vietnamese patients with CRC, including a strikingly high rate of MSI-H and its high co-existence with KRAS and BRAF mutations, which should be carefully considered in the future therapeutics for this type of cancer.
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Affiliation(s)
- Ha Thi Nguyen
- Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam.,Faculty of Medicine, Duy Tan University, Danang 550000, Vietnam
| | - Do Thanh Le
- Institute for Global Health Innovations, Duy Tan University, Danang 550000, Vietnam.,Faculty of Pharmacy, Duy Tan University, Danang 550000, Vietnam
| | - Quan Hong Duong
- Laboratory Center, Hanoi University of Public Heath, Hanoi 100000, Vietnam
| | - Vinay Bharadwaj Tatipamula
- Institute of Research and Development, Duy Tan University, Danang 550000, Vietnam.,Faculty of Pharmacy, Duy Tan University, Danang 550000, Vietnam
| | - Bang Van Nguyen
- Anapathology Department, Hue Central Hospital, Hue 530000, Vietnam
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25
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Ogunwobi OO, Mahmood F, Akingboye A. Biomarkers in Colorectal Cancer: Current Research and Future Prospects. Int J Mol Sci 2020; 21:E5311. [PMID: 32726923 PMCID: PMC7432436 DOI: 10.3390/ijms21155311] [Citation(s) in RCA: 165] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2020] [Revised: 07/12/2020] [Accepted: 07/20/2020] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is a leading cause of death worldwide, despite progress made in detection and management through surgery, chemotherapy, radiotherapy, and immunotherapy. Novel therapeutic agents have improved survival in both the adjuvant and advanced disease settings, albeit with an increased risk of toxicity and cost. However, metastatic disease continues to have a poor long-term prognosis and significant challenges remain due to late stage diagnosis and treatment failure. Biomarkers are a key tool in early detection, prognostication, survival, and predicting treatment response. The past three decades have seen advances in genomics and molecular pathology of cancer biomarkers, allowing for greater individualization of therapy with a positive impact on survival outcomes. Clinically useful predictive biomarkers aid clinical decision making, such as the presence of KRAS gene mutations predicting benefit from epidermal growth factor receptor (EGFR) inhibiting antibodies. However, few biomarkers have been translated into clinical practice highlighting the need for further investigation. We review a range of protein, DNA and RNA-based biomarkers under investigation for diagnostic, predictive, and prognostic properties for CRC. In particular, long non-coding RNAs (lncRNA), have been investigated as biomarkers in a range of cancers including colorectal cancer. Specifically, we evaluate the potential role of lncRNA plasmacytoma variant translocation 1 (PVT1), an oncogene, as a diagnostic, prognostic, and therapeutic biomarker in colorectal cancer.
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Affiliation(s)
- Olorunseun O. Ogunwobi
- Department of Biological Sciences, Hunter College of The City University of New York, New York, NY 10065, USA
- Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 10021, USA
| | - Fahad Mahmood
- The Dudley Group Hospitals, Russells Hall Hospital, The Dudley Group NHS Foundation Trust, Dudley, West Midlands DY1 2HQ, UK;
| | - Akinfemi Akingboye
- The Dudley Group Hospitals, Russells Hall Hospital, The Dudley Group NHS Foundation Trust, Dudley, West Midlands DY1 2HQ, UK;
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26
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Baraibar I, Ros J, Mulet N, Salvà F, Argilés G, Martini G, Cuadra JL, Sardo E, Ciardiello D, Tabernero J, Élez E. Incorporating traditional and emerging biomarkers in the clinical management of metastatic colorectal cancer: an update. Expert Rev Mol Diagn 2020; 20:653-664. [PMID: 32552041 DOI: 10.1080/14737159.2020.1782194] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
INTRODUCTION Molecular profiling has led to significantly longer survival in metastatic colorectal cancer (mCRC) patients. Clinical guidelines recommend testing for KRAS/NRAS, BRAF and MSI status, and new biomarkers such as HER2 amplification and NTRK fusions have emerged more recently in refractory CRC, supported by overwhelming clinical relevance. These biomarkers can guide treatment management to improve clinical outcomes in these patients. AREAS COVERED Preclinical and clinical data over the last decade were reviewed for known and novel biomarkers with clinical implications in refractory CRC. Molecular alterations are described for classic and novel biomarkers, and data for completed and ongoing studies with targeted and immunotherapies are presented. EXPERT OPINION Use of targeted therapies based on biomarker testing in CRC has enabled impressive improvements in clinical outcomes in refractory patients. BRAF, MSI, NRAS and KRAS should be tested upfront in all patients given their indisputable therapeutic implications. Other molecular alterations such as HER2 and NTRK are emerging. Testing for these alterations may further improve outcomes for refractory CRC patients. Nonetheless, many key aspects remain to be defined including the optimal timing and technique for testing, the most adequate panel, and whether all patients should be tested for all alterations.
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Affiliation(s)
- Iosune Baraibar
- Department of Medical Oncology, Vall d'Hebron University Hospital , Barcelona, Spain.,Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona, Spain
| | - Javier Ros
- Department of Medical Oncology, Vall d'Hebron University Hospital , Barcelona, Spain.,Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona, Spain
| | - Nuria Mulet
- Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona, Spain.,Department of Medical Oncology, Institut Català D' oncologia-IDIBELL , Barcelona, Spain
| | - Francesc Salvà
- Department of Medical Oncology, Vall d'Hebron University Hospital , Barcelona, Spain.,Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona, Spain
| | - Guillem Argilés
- Department of Medical Oncology, Vall d'Hebron University Hospital , Barcelona, Spain.,Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona, Spain
| | - Giulia Martini
- Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona, Spain.,Dipartimento di Medicina di Precisione, Università Degli Studi Della Campania Luigi Vanvitelli , Naples, Italy
| | | | - Emilia Sardo
- Department of Medical Oncology, Vall d'Hebron University Hospital , Barcelona, Spain
| | - Davide Ciardiello
- Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona, Spain.,Dipartimento di Medicina di Precisione, Università Degli Studi Della Campania Luigi Vanvitelli , Naples, Italy
| | - Josep Tabernero
- Department of Medical Oncology, Vall d'Hebron University Hospital , Barcelona, Spain.,Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona, Spain
| | - Elena Élez
- Department of Medical Oncology, Vall d'Hebron University Hospital , Barcelona, Spain.,Department of Medical Oncology, Vall d'Hebron Institute of Oncology (VHIO) , Barcelona, Spain
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27
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Moradi A, Pourseif MM, Jafari B, Parvizpour S, Omidi Y. Nanobody-based therapeutics against colorectal cancer: Precision therapies based on the personal mutanome profile and tumor neoantigens. Pharmacol Res 2020; 156:104790. [DOI: 10.1016/j.phrs.2020.104790] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2020] [Revised: 03/07/2020] [Accepted: 03/31/2020] [Indexed: 12/19/2022]
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28
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Varshavi D, Varshavi D, McCarthy N, Veselkov K, Keun HC, Everett JR. Metabolic characterization of colorectal cancer cells harbouring different KRAS mutations in codon 12, 13, 61 and 146 using human SW48 isogenic cell lines. Metabolomics 2020; 16:51. [PMID: 32300895 PMCID: PMC7162829 DOI: 10.1007/s11306-020-01674-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2019] [Accepted: 04/02/2020] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) mutations occur in approximately one-third of colorectal (CRC) tumours and have been associated with poor prognosis and resistance to some therapeutics. In addition to the well-documented pro-tumorigenic role of mutant Ras alleles, there is some evidence suggesting that not all KRAS mutations are equal and the position and type of amino acid substitutions regulate biochemical activity and transforming capacity of KRAS mutations. OBJECTIVES To investigate the metabolic signatures associated with different KRAS mutations in codons 12, 13, 61 and 146 and to determine what metabolic pathways are affected by different KRAS mutations. METHODS We applied an NMR-based metabonomics approach to compare the metabolic profiles of the intracellular extracts and the extracellular media from isogenic human SW48 CRC cell lines with different KRAS mutations in codons 12 (G12D, G12A, G12C, G12S, G12R, G12V), 13 (G13D), 61 (Q61H) and 146 (A146T) with their wild-type counterpart. We used false discovery rate (FDR)-corrected analysis of variance (ANOVA) to determine metabolites that were statistically significantly different in concentration between the different mutants. RESULTS CRC cells carrying distinct KRAS mutations exhibited differential metabolic remodelling, including differences in glycolysis, glutamine utilization and in amino acid, nucleotide and hexosamine metabolism. CONCLUSIONS Metabolic differences among different KRAS mutations might play a role in their different responses to anticancer treatments and hence could be exploited as novel metabolic vulnerabilities to develop more effective therapies against oncogenic KRAS.
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Affiliation(s)
- Dorna Varshavi
- Medway Metabonomics Research Group, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK
| | - Dorsa Varshavi
- Medway Metabonomics Research Group, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK
| | - Nicola McCarthy
- Horizon Discovery Ltd., Cambridge Research Park, 8100 Beach Dr, Waterbeach, Cambridge, CB25 9TL, UK
| | - Kirill Veselkov
- Department of Surgery and Cancer, Faculty of Medicine, Imperial College, London, SW7 2AZ, UK
| | - Hector C Keun
- Department of Surgery and Cancer, Imperial College London, Hammersmith Hospital Campus, London, W12 ONN, UK
| | - Jeremy R Everett
- Medway Metabonomics Research Group, University of Greenwich, Chatham Maritime, Kent, ME4 4TB, UK.
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29
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Hon KW, Othman N, Hanif EAM, Nasir SN, Razak NSA, Jamal R, Abu N. Predictive biomarkers of drug resistance in colorectal cancer—Recent updates. DRUG RESISTANCE IN COLORECTAL CANCER: MOLECULAR MECHANISMS AND THERAPEUTIC STRATEGIES 2020:135-151. [DOI: 10.1016/b978-0-12-819937-4.00008-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/02/2023]
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30
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Ahmed E, Masud MK, Hossain MSA, Na J, Sina AAI, Yamauchi Y, Trau M. Nanostructured mesoporous gold electrodes detect protein phosphorylation in cancer with electrochemical signal amplification. Analyst 2020; 145:6639-6648. [DOI: 10.1039/d0an01096k] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
A nanostructured mesoporous gold electrode is demonstrated to detect the phosphorylated protein over non-phosphorylated in cancer using electrochemical signal amplification through differential pulse voltammetry in the presence of the [Fe(CN)6]3−/4−.
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Affiliation(s)
- Emtiaz Ahmed
- Australian Institute for Bioengineering and Nanotechnology (AIBN)
- The University of Queensland
- Brisbane
- Australia
| | - Mostafa Kamal Masud
- Australian Institute for Bioengineering and Nanotechnology (AIBN)
- The University of Queensland
- Brisbane
- Australia
| | - Md. Shahriar A. Hossain
- Australian Institute for Bioengineering and Nanotechnology (AIBN)
- The University of Queensland
- Brisbane
- Australia
- School of Mechanical and Mining Engineering
| | - Jongbeom Na
- Australian Institute for Bioengineering and Nanotechnology (AIBN)
- The University of Queensland
- Brisbane
- Australia
| | - Abu Ali Ibn Sina
- Australian Institute for Bioengineering and Nanotechnology (AIBN)
- The University of Queensland
- Brisbane
- Australia
| | - Yusuke Yamauchi
- Australian Institute for Bioengineering and Nanotechnology (AIBN)
- The University of Queensland
- Brisbane
- Australia
- School of Chemical Engineering
| | - Matt Trau
- Australian Institute for Bioengineering and Nanotechnology (AIBN)
- The University of Queensland
- Brisbane
- Australia
- School of Chemistry and Molecular Biosciences
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31
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Miranda R, Silva T, Forones N. High-resolution melting for detecting KRAS mutations in colorectal cancer. Biomed Rep 2019; 11:269-273. [DOI: 10.3892/br.2019.1254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 11/01/2019] [Indexed: 12/24/2022] Open
Affiliation(s)
- Raelson Miranda
- Gastroenterology Division, Department of Medicine, Gastrointestinal Oncology Group, Universidade Federal de Sao Paulo, Sao Paulo CEP 04023900, Brazil
| | - Tiago Silva
- Gastroenterology Division, Department of Medicine, Gastrointestinal Oncology Group, Universidade Federal de Sao Paulo, Sao Paulo CEP 04023900, Brazil
| | - Nora Forones
- Gastroenterology Division, Department of Medicine, Gastrointestinal Oncology Group, Universidade Federal de Sao Paulo, Sao Paulo CEP 04023900, Brazil
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32
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Preclinical Modelling of PDA: Is Organoid the New Black? Int J Mol Sci 2019; 20:ijms20112766. [PMID: 31195689 PMCID: PMC6600483 DOI: 10.3390/ijms20112766] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2019] [Revised: 05/31/2019] [Accepted: 06/03/2019] [Indexed: 12/17/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDA) is a malignancy of the exocrine pancreas with the worst prognosis among all solid tumours, and soon to become the second leading cause of cancer-related deaths. A more comprehensive understanding of the molecular mechanisms underlying this disease is crucial to the development of diagnostic tools as well as to the identification of more effective therapies. High-frequency mutations in PDA occur in “undruggable” genes, and molecular subtyping based on bulk transcriptome analysis does not yet nominate valid therapeutic intervention strategies. Genome-wide sequencing studies have also demonstrated a considerable intra- and inter-patient’s genetic heterogeneity, which further complicate this dire scenario. More than in other malignancies, functionalization of the PDA genome and preclinical modelling at the individual patient level appear necessary to substantially improve survival rates for pancreatic cancer patients. Traditional human PDA models, including monolayer cell cultures and patient-derived xenografts, have certainly led to valuable biological insights in the past years. However, those model systems suffer from several limitations that have contributed to the lack of concordance between preclinical and clinical studies for PDA. Pancreatic ductal organoids have recently emerged as a reliable culture system to establish models from both normal and neoplastic pancreatic tissues. Pancreatic organoid cultures can be efficiently generated from small tissue biopsies, which opens up the possibility of longitudinal studies in individual patients. A proof-of-concept study has demonstrated that patient-derived PDA organoids are able to predict responses to conventional chemotherapy. The use of this three-dimensional culture system has already improved our understanding of PDA biology and promises to implement precision oncology by enabling the alignment of preclinical and clinical platforms to guide therapeutic intervention in PDA.
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33
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Chauhan N, Mulcahy MF, Salem R, Benson Iii AB, Boucher E, Bukovcan J, Cosgrove D, Laframboise C, Lewandowski RJ, Master F, El-Rayes B, Strosberg JR, Sze DY, Sharma RA. TheraSphere Yttrium-90 Glass Microspheres Combined With Chemotherapy Versus Chemotherapy Alone in Second-Line Treatment of Patients With Metastatic Colorectal Carcinoma of the Liver: Protocol for the EPOCH Phase 3 Randomized Clinical Trial. JMIR Res Protoc 2019; 8:e11545. [PMID: 30664496 PMCID: PMC6354199 DOI: 10.2196/11545] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2018] [Revised: 11/09/2018] [Accepted: 11/09/2018] [Indexed: 12/21/2022] Open
Abstract
Background Colorectal cancer is one of the most common cancers and causes of cancer-related death. Up to approximately 70% of patients with metastatic colorectal cancer (mCRC) have metastases to the liver at initial diagnosis. Second-line systemic treatment in mCRC can prolong survival after development of disease progression during or after first-line treatment and in those who are intolerant to first-line treatment. Objective The objective of this study is to evaluate the efficacy and safety of transarterial radioembolization (TARE) with TheraSphere yttrium-90 (90Y) glass microspheres combined with second-line therapy in patients with mCRC of the liver who had disease progression during or after first-line chemotherapy. Methods EPOCH is an open-label, prospective, multicenter, randomized, phase 3 trial being conducted at up to 100 sites in the United States, Canada, Europe, and Asia. Eligible patients have mCRC of the liver and disease progression after first-line chemotherapy with either an oxaliplatin-based or irinotecan-based regimen and are eligible for second-line chemotherapy with the alternate regimen. Patients were randomized 1:1 to the TARE group (chemotherapy with TARE in place of the second chemotherapy infusion and subsequent resumption of chemotherapy) or the control group (chemotherapy alone). The addition of targeted agents is permitted. The primary end points are progression-free survival and hepatic progression-free survival. The study objective will be considered achieved if at least one primary end point is statistically significant. Secondary end points are overall survival, time to symptomatic progression defined as Eastern Cooperative Oncology Group Performance Status score of 2 or higher, objective response rate, disease control rate, quality-of-life assessment by the Functional Assessment of Cancer Therapy-Colorectal Cancer questionnaire, and adverse events. The study is an adaptive trial, comprising a group sequential design with 2 interim analyses with a planned maximum of 420 patients. The study is designed to detect a 2.5-month increase in median progression-free survival, from 6 months in the control group to 8.5 months in the TARE group (hazard ratio [HR] 0.71), and a 3.5-month increase in median hepatic progression-free survival time, from 6.5 months in the control group to 10 months in the TARE group (HR 0.65). On the basis of simulations, the power to detect the target difference in either progression-free survival or hepatic progression-free survival is >90%, and the power to detect the target difference in each end point alone is >80%. Results Patient enrollment ended in October 2018. The first interim analysis in June 2018 resulted in continuation of the study without any changes. Conclusions The EPOCH study may contribute toward the establishment of the role of combination therapy with TARE and oxaliplatin- or irinotecan-based chemotherapy in the second-line treatment of mCRC of the liver. Trial Registration ClinicalTrials.gov NCT01483027; https://clinicaltrials.gov/ct2/show/NCT01483027 (Archived by WebCite at http://www.webcitation.org/734A6PAYW) International Registered Report Identifier (IRRID) RR1-10.2196/11545
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Affiliation(s)
- Nikhil Chauhan
- Research and Development, BTG International group companies, London, United Kingdom
| | - Mary F Mulcahy
- Division of Hematology and Oncology, Department of Medicine, Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
| | - Riad Salem
- Division of Hematology and Oncology, Department of Medicine, Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States.,Section of Interventional Radiology, Department of Radiology, Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States.,Division of Transplant Surgery, Department of Surgery, Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
| | - Al B Benson Iii
- Division of Hematology and Oncology, Department of Medicine, Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States.,Northwestern Medical Group, Feinberg School of Medicine, Northwestern Memorial Hospital, Chicago, IL, United States
| | - Eveline Boucher
- Research and Development, BTG International group companies, London, United Kingdom
| | - Janet Bukovcan
- Research and Development, BTG International group companies, London, United Kingdom
| | - David Cosgrove
- Division of Medical Oncology, Vancouver Cancer Center, Compass Oncology, Vancouver, WA, United States
| | - Chantal Laframboise
- Research and Development, BTG International group companies, London, United Kingdom
| | - Robert J Lewandowski
- Division of Hematology and Oncology, Department of Medicine, Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States.,Section of Interventional Radiology, Department of Radiology, Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States.,Division of Transplant Surgery, Department of Surgery, Robert H Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL, United States
| | - Fayaz Master
- Research and Development, BTG International group companies, London, United Kingdom
| | - Bassel El-Rayes
- Winship Cancer Institute, Emory University, Atlanta, GA, United States.,Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, United States
| | | | - Daniel Y Sze
- Interventional Radiology, Stanford University Medical Center, Stanford, CA, United States
| | - Ricky A Sharma
- National Institute for Health Research University College London Hospitals Biomedical Research Centre, UCL Cancer Institute, London, United Kingdom
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Abbaszadegan MR, Moghbeli M. Genetic and molecular origins of colorectal Cancer among the Iranians: an update. Diagn Pathol 2018; 13:97. [PMID: 30579343 PMCID: PMC6303916 DOI: 10.1186/s13000-018-0774-0] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2018] [Accepted: 12/05/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Colorectal cancer (CRC) is one the leading causes of cancer related deaths among Iranians. Despite the various progresses in new therapeutic methods, it has still a low rate of survival. This high ratio of mortality is mainly related to the late diagnosis, in which the patients refer for treatment in advanced stages of tumor. MAIN BODY: colorectal cancer progression is largely associated with molecular and genetic bases. Although Iran has a high ratio of CRC mortality, there is not an efficient genetic panel for detection and prognosis. Therefore, it is critical to introduce new diagnostic markers with ability to detect in early stages. CONCLUSION Present review summarizes all of the genetic and epigenetic factors which are reported in CRC until now among the Iranian patients to pave the way of incorporation of new ethnic specific markers into the clinical practice and development of new targeted therapeutic methods.
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Affiliation(s)
| | - Meysam Moghbeli
- Department of Modern Sciences and Technologies, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Yi M, Zhu R, Stephens RM. GradientScanSurv-An exhaustive association test method for gene expression data with censored survival outcome. PLoS One 2018; 13:e0207590. [PMID: 30517129 PMCID: PMC6281197 DOI: 10.1371/journal.pone.0207590] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2018] [Accepted: 11/03/2018] [Indexed: 12/22/2022] Open
Abstract
Accurate assessment of the association between continuous variables such as gene expression and survival is a critical aspect of precision medicine. In this report, we provide a review of some of the available survival analysis and validation tools by referencing published studies that have utilized these tools. We have identified pitfalls associated with the assumptions inherent in those applications that have the potential to impact scientific research through their potential bias. In order to overcome these pitfalls, we have developed a novel method that enables the logrank test method to handle continuous variables that comprehensively evaluates survival association with derived aggregate statistics. This is accomplished by exhaustively considering all the cutpoints across the full expression gradient. Direct side-by-side comparisons, global ROC analysis, and evaluation of the ability to capture relevant biological themes based on current understanding of RAS biology all demonstrated that the new method shows better consistency between multiple datasets of the same disease, better reproducibility and robustness, and better detection power to uncover biological relevance within the selected datasets over the available survival analysis methods on univariate gene expression and penalized linear model-based methods.
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Affiliation(s)
- Ming Yi
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States of America
- * E-mail:
| | - Ruoqing Zhu
- Department of Statistics, University of Illinois Urbana-Champaign, Champaign, IL, United States of America
| | - Robert M. Stephens
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Frederick, MD, United States of America
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Ording AG, Öztürk B, Spindler KLG, Sørensen HT, McCusker M, Ehrenstein V. KRAS mutation status, comorbidity, and mortality in patients with metastatic colorectal cancer in Denmark. Acta Oncol 2018; 57:1727-1729. [PMID: 30264648 DOI: 10.1080/0284186x.2018.1503420] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/28/2022]
Affiliation(s)
- Anne Gulbech Ording
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Buket Öztürk
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Karen-Lise Garm Spindler
- Department of Experimental Clinical Oncology, Aarhus University Hospital, Aarhus, Denmark
- Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
| | - Henrik Toft Sørensen
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
| | - Margaret McCusker
- Diagnostics Information Solutions, F Hoffmann-La Roche AG, Pleasanton, CA, USA
| | - Vera Ehrenstein
- Department of Clinical Epidemiology, Aarhus University Hospital, Aarhus, Denmark
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Molinari C, Marisi G, Passardi A, Matteucci L, De Maio G, Ulivi P. Heterogeneity in Colorectal Cancer: A Challenge for Personalized Medicine? Int J Mol Sci 2018; 19:E3733. [PMID: 30477151 PMCID: PMC6321493 DOI: 10.3390/ijms19123733] [Citation(s) in RCA: 160] [Impact Index Per Article: 22.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 11/19/2018] [Accepted: 11/20/2018] [Indexed: 12/15/2022] Open
Abstract
High inter-patient variability and high spatial heterogeneity are features of colorectal cancer (CRC). This may influence the molecular characterization of tumor tissue, now mandatory for patients with metastatic CRC who are candidates for treatment with an anti-EGFR mAb, as false-negative results can occur, leading to non optimal therapy. Moreover, temporal molecular heterogeneity during treatment is known to influence the response to therapy and prognosis. We present a literature overview of advances made in characterizing molecular heterogeneity in CRC, underlining that the analysis of liquid biopsy could represent an efficient non-invasive tool to overcome the problem. We believe that understanding CRC heterogeneity is fundamental for a more accurate diagnosis, for selecting the best targets to ensure prolonged antitumor response, and for monitoring minimal residual disease and the onset of resistance to therapy, all essential components of successful personalized treatment.
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Affiliation(s)
- Chiara Molinari
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Giorgia Marisi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Alessandro Passardi
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Laura Matteucci
- Department of Medical Oncology, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Giulia De Maio
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
| | - Paola Ulivi
- Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.
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Comprehensive Validation of Snapback Primer-Based Melting Curve Analysis to Detect Nucleotide Variation in the Codon 12 and 13 of KRAS Gene. BIOMED RESEARCH INTERNATIONAL 2018; 2018:8727941. [PMID: 30406144 PMCID: PMC6199860 DOI: 10.1155/2018/8727941] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Accepted: 08/13/2018] [Indexed: 01/05/2023]
Abstract
Background KRAS genotyping in tumor samples is a decisive clinical test for the anti-EGFR therapy management. However, the complexity of KRAS mutation landscape across different cancer types and the mosaic effect caused by cancer cellularity and heterogeneity make the choice of KRAS genotyping method a challenging topic in the clinical practice. Methods We depicted the landscape of somatic KRAS mutation in 7,844 primary tumors and 10,336 metastatic tumors across over 30 types of cancer using the Cancer Genome Atlas (TCGA) and Integrated Mutation Profiling of Actionable Cancer Targets (MSKCC-IMPACT) databases, respectively. A snapback primer assay based on melting curve analysis was developed to detect the most common somatic mutations in KRAS codons 12 and 13. The sensitivity and accuracy of the method was validated by genotyping 100 colorectal cancer (CRC) samples, in comparison with Sanger sequencing and T-A cloning sequencing. Results Pancreas adenocarcinoma (somatic mutation frequency 90.6%), colorectal adenocarcinoma (42.5%), and lung adenocarcinoma (32.6%) are the top three most KRAS mutant primary cancer types. The metastatic tumors showed a higher prevalence (90.99% versus 66.31%) and diversity of KRAS mutation compared with the primary tumors. Mutations in codons 12 and 13 are the predominant genetic alteration in KRAS (84.15% for TCGA and 86.13% for MSK-IMPACT). Moreover, KRAS mutation is highly correlated with the overall survival of patients with metastatic cancer. The snapback primer assay showed a more favorable performance in enriching and detecting the KRAS codon 12 and 13 mutation (1% mutation load) compared with Sanger sequencing (20% mutation load and 7% false-negative rate). Conclusions KRAS mutation pattern is highly diverse among different cancer types and is associated with the survival of patients with metastatic cancers. The snapback primer assay is a reliable, sensitive method to detect the major mutant KRAS alleles, which might facilitate the effective cancer treatment decisions.
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KRAS, KIT and TP53 mutations in mother's and daughter's gastric cardia adenocarcinomas. GASTROENTEROLOGY REVIEW 2018; 13:76-79. [PMID: 29657615 PMCID: PMC5894445 DOI: 10.5114/pg.2018.72572] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 07/31/2017] [Accepted: 12/06/2017] [Indexed: 12/11/2022]
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Jeong KY, Kim EK, Park MH, Kim HM. Perspective on Cancer Therapeutics Utilizing Analysis of Circulating Tumor Cells. Diagnostics (Basel) 2018; 8:23. [PMID: 29641512 PMCID: PMC6023425 DOI: 10.3390/diagnostics8020023] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 04/03/2018] [Accepted: 04/09/2018] [Indexed: 12/19/2022] Open
Abstract
Various methods are available for cancer screening, and the methods are performed depending on the origin site of cancer. Among these methods, biopsy followed by medical imaging is the most common. After cancer progression is determined, an optimal treatment-such as surgery, chemotherapy, and/or radiation therapy-is selected. A new assay has been developed that detects circulating tumor cells (CTCs). Tracking changes in CTCs may reveal important tumoral sensitivity information or resistance patterns to specific regimens and prompt changes in therapy on a personalized basis. Characterization of CTCs at the DNA, RNA, and protein levels is important for gaining insight for clinical applications. A small number of CTCs can be analyzed to obtain genome information such as the progression of cancer including metastasis, even in a single cluster. Although many clinical studies, particularly CTC enumeration and detection of specific oncogene expression, have increased the success rate of diagnosis and predicting prognosis, there is no consensus regarding the technical approaches and various aspects of the methodology, making it difficult to standardize optimal methods for CTC analysis. However, ongoing technological advances are currently being achieved and large-scale clinical studies are being conducted. Applying CTC analysis in the clinic would be very useful for advancing diagnosis, prognosis prediction, and therapeutics.
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Affiliation(s)
- Keun-Yeong Jeong
- R&D Division, Metimedi Pharmaceuticals Co., 263, Central-ro, Yeonsu-Gu, Incheon 22006, Korea.
| | - Eun Kyung Kim
- R&D Division, Metimedi Pharmaceuticals Co., 263, Central-ro, Yeonsu-Gu, Incheon 22006, Korea.
| | - Min Hee Park
- R&D Division, Metimedi Pharmaceuticals Co., 263, Central-ro, Yeonsu-Gu, Incheon 22006, Korea.
| | - Hwan Mook Kim
- Gachon Institute of Pharmaceutical Science, Gachon University, 191, Hambangmoe-ro, Yeonsu-gu, Incheon 21936, Korea.
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Perspective on Cancer Therapeutics Utilizing Analysis of Circulating Tumor Cells. DIAGNOSTICS (BASEL, SWITZERLAND) 2018. [PMID: 29641512 DOI: 10.3390/diagnostics8020023.] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Various methods are available for cancer screening, and the methods are performed depending on the origin site of cancer. Among these methods, biopsy followed by medical imaging is the most common. After cancer progression is determined, an optimal treatment-such as surgery, chemotherapy, and/or radiation therapy-is selected. A new assay has been developed that detects circulating tumor cells (CTCs). Tracking changes in CTCs may reveal important tumoral sensitivity information or resistance patterns to specific regimens and prompt changes in therapy on a personalized basis. Characterization of CTCs at the DNA, RNA, and protein levels is important for gaining insight for clinical applications. A small number of CTCs can be analyzed to obtain genome information such as the progression of cancer including metastasis, even in a single cluster. Although many clinical studies, particularly CTC enumeration and detection of specific oncogene expression, have increased the success rate of diagnosis and predicting prognosis, there is no consensus regarding the technical approaches and various aspects of the methodology, making it difficult to standardize optimal methods for CTC analysis. However, ongoing technological advances are currently being achieved and large-scale clinical studies are being conducted. Applying CTC analysis in the clinic would be very useful for advancing diagnosis, prognosis prediction, and therapeutics.
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ROR1 expression as a biomarker for predicting prognosis in patients with colorectal cancer. Oncotarget 2018; 8:32864-32872. [PMID: 28427197 PMCID: PMC5464834 DOI: 10.18632/oncotarget.15860] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2016] [Accepted: 02/07/2017] [Indexed: 02/05/2023] Open
Abstract
There is a lack of reliable prognosis biomarker in the current treatment of colorectal cancer. The receptor-tyrosine-kinase-like orphan receptor 1 (ROR1) is overexpressed and associated with poor prognosis in certain tumors. This study aimed to explore the prognostic significance of ROR1 in colorectal cancer. Western blot analysis and immunohistochemistry showed that the expression of ROR1 in colorectal cancer was significantly higher than that in the adjacent normal tissues. ROR1 expression was positively associated with the clinical stage and lymph-node metastasis (p < 0.01). Kaplan-Meier survival analysis revealed that patients with higher ROR1 expression had a significantly shorter overall survival (p < 0.01). Multivariate Cox regression analysis confirmed that ROR1 is an independent prognostic marker in colorectal cancer (p = 0.002, HR = 2.08, 95% CI: 1.314–3.292). Thus, our study demonstrated that ROR1 expression is correlated with malignant attributes and may serve as a novel prognostic marker and therapeutic target for colorectal cancer.
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Roh MS, Lee HW, Jung SB, Kim K, Lee EH, Park MI, Lee JS, Kim MS. Expression of miR-200c and its clinicopathological significance in patients with colorectal cancer. Pathol Res Pract 2018; 214:350-355. [PMID: 29496312 DOI: 10.1016/j.prp.2018.01.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 01/06/2018] [Accepted: 01/24/2018] [Indexed: 01/21/2023]
Abstract
MicroRNA-200c (miR-200c) is known to play a pivotal role in the regulation of epithelial-to-mesenchymal and mesenchymal-to-epithelial transition processes. However, the biological function of miR-200c in human carcinogenesis remains controversial. We examined the association of miR-200c expression with various clinicopathological factors, including KRAS mutation status and survival, in patients with colorectal cancer (CRC). The expression level of miR-200c was evaluated in 109 paired CRC and normal tissue samples using quantitative reverse transcription polymerase chain reaction. The KRAS mutation status of the CRC samples was determined using the PNAClamp™ KRAS Mutation Detection kit. Compared with the normal tissue group, miR-200c expression was significantly upregulated in the CRCs (P < .001). The expression of miR-200c was increased in CRCs with higher grade (P = .009), advanced stage (P = .042), and lymphovascular invasion (P = .003). Thirty-one CRCs (28.4%) had KRAS mutations in codon 12 or 13. CRCs with KRAS mutations had significantly higher miR-200c expression than CRCs with wild-type KRAS (P = .003). In survival analysis, high miR-200c expression was correlated with worse overall survival (P = .017) and recurrence-free survival (P = .048). Our results indicate that miR-200c is involved in tumor progression and aggressiveness in CRCs, and this oncogenic role of miR-200c may be triggered by activation of the KRAS signaling pathway.
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Affiliation(s)
- Mee Sook Roh
- Department of Pathology, Dong-A University College of Medicine, Busan, South Korea
| | - Hyoun Wook Lee
- Department of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea.
| | - Sang Bong Jung
- Department of Clinical Laboratory Science, Dong-Eui Institute of Technology, Busan, South Korea
| | - Kyungeun Kim
- Department of Pathology, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, South Korea
| | - Eun Hee Lee
- Department of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea
| | - Moon-Il Park
- Department of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea
| | - Jae Seok Lee
- Department of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea
| | - Mee-Seon Kim
- Department of Pathology, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, South Korea
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Abraham J, Singh S, Joshi S. Liquid biopsy - emergence of a new era in personalized cancer care. ACTA ACUST UNITED AC 2018. [DOI: 10.1186/s41241-018-0053-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Rossi S, Sbaraglia M, Dell'Orto MC, Gasparotto D, Cacciatore M, Boscato E, Carraro V, Toffolatti L, Gallina G, Niero M, Pilozzi E, Mandolesi A, Sessa F, Sonzogni A, Mancini C, Mazzoleni G, Romeo S, Maestro R, Dei Tos AP. Concomitant KIT/BRAF and PDGFRA/BRAF mutations are rare events in gastrointestinal stromal tumors. Oncotarget 2017; 7:30109-18. [PMID: 27097112 PMCID: PMC5058667 DOI: 10.18632/oncotarget.8768] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2015] [Accepted: 04/04/2016] [Indexed: 01/13/2023] Open
Abstract
AIM The BRAF mutation is a rare pathogenetic alternative to KIT/PDGFRA mutation in GIST and causes Imatinib resistance. A recent description of KIT and BRAF mutations co-occurring in an untreated GIST has challenged the concept of their being mutually exclusive and may account for ab initio resistance to Imatinib, even in the presence of Imatinib-sensitive KIT mutations. BRAF sequencing is generally limited to KIT/PDGFRA wild-type cases. Hence, the frequency of concomitant mutations may be underestimated. METHODS We screened for KIT (exon 9, 11, 13, 17), PDGFRA (exon 12,14, 18) and BRAF (exon 15) mutations a series of 407 GIST. Additionally, we evaluated the BRAF V600E mutation-specific antibody, VE1, as a surrogate for V600E mutation, on a series of 313 GIST (24 on whole sections, 288 cases on tissue array), including 6 cases molecularly ascertained to carry the BRAF V600E mutation. RESULTS No concomitant KIT/BRAF or PDGFRA/BRAF mutations were detected. BRAF mutation was detected only in one case, wild-type for KIT/PDGFRA. All the 6 BRAF-mutant cases stained positive with the VE1 antibody. A weak VE1 expression was observed in 14/287 (4.9%) BRAF wild-type cases, as observed also in 2/6 BRAF-mutant cases. Overall in our series, sensitivity and specificity of the VE1 antobody were 100% and 95.1%, respectively. CONCLUSION The concomitance of BRAF mutation with either KIT or PDGFRA mutation is rare in GIST. In these tumors, moderate/strong VE1 immunoreactivity is a valuable surrogate for molecular analysis. Instead, genotyping is warranted in the presence of weak VE1 staining.
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Affiliation(s)
- Sabrina Rossi
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Marta Sbaraglia
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Marta Campo Dell'Orto
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | | | - Matilde Cacciatore
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Elena Boscato
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Valentina Carraro
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Luisa Toffolatti
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Giovanna Gallina
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Monia Niero
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | - Emanuela Pilozzi
- Department of Clinical and Molecular Medicine, University of Rome "La Sapienza", Rome, Italy
| | - Alessandra Mandolesi
- Department of Pathology, University of Marche, Ancona School of Medicine, Ancona, Italy
| | - Fausto Sessa
- Department of Pathology, Macchi Fondation, Varese, Italy
| | | | - Cristina Mancini
- Department of Pathology, Azienda Ospedaliera-Universitaria, Parma, Italy
| | | | - Salvatore Romeo
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
| | | | - Angelo P Dei Tos
- Department of Pathology and Molecular Genetics, Treviso General Hospital, Treviso, Italy
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Sugai T, Takahashi Y, Eizuka M, Sugimoto R, Fujita Y, Habano W, Otsuka K, Sasaki A, Yamamoto E, Matsumoto T, Suzuki H. Molecular profiling and genome-wide analysis based on somatic copy number alterations in advanced colorectal cancers. Mol Carcinog 2017; 57:451-461. [PMID: 29230882 PMCID: PMC5814737 DOI: 10.1002/mc.22769] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2017] [Revised: 11/18/2017] [Accepted: 11/20/2017] [Indexed: 12/13/2022]
Abstract
To characterize somatic alterations in colorectal cancer (CRC), we conducted a genome-scale analysis of 106 CRC specimens. We assessed comprehensive somatic copy number alterations (SCNAs) in these CRC specimens. In addition, we examined microsatellite instability (MSI; low and high), genetic mutations (KRAS, BRAF, TP53, and PIK3CA), and DNA methylation status (classified into low, intermediate, and high type). We stratified molecular alterations in the CRCs using a hierarchical cluster analysis. The examined CRCs could be categorized into three subgroups using hierarchical cluster analysis. Tumors in subgroup 1 were characterized by a low frequency of SCNAs and a high frequency of MSI-high status, whereas tumors in subgroups 2 and 3 were closely associated with a high frequency of SCNAs. Tumors in subgroup 1 were preferentially present in the right-sided colon and showed frequent MSI-high status. Subgroup 3 was distinguished by specific alterations, including gains at 1q23-44, 1p11-36, 10q11-26, 10p11-13, 12q24-24, and 13q33-33. In contrast, tumors in subgroup 2 were characterized by copy-neutral LOH at 12p12-13, 1q24-25, and 10q22. In addition, KRAS mutations were more frequently found in subgroup 3 than in subgroup 1. TP53 mutations and intermediate levels of DNA methylation were common alterations in the three subgroups. SCNAs contributed to sporadic CRC, and there were three subgroups based on SCNAs that played a different role in driving the development of this disease.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Yayoi Takahashi
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Yasuko Fujita
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Wataru Habano
- Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Morioka, Japan
| | - Kouki Otsuka
- Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Akira Sasaki
- Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Eiichiro Yamamoto
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Sapporo, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, School of Medicine, Iwate Medical University, Morioka, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Sapporo, Japan
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Wei LH, Lin JM, Chu JF, Chen HW, Li QY, Peng J. Scutellaria barbata D. Don inhibits colorectal cancer growth via suppression of Wnt/β-catenin signaling pathway. Chin J Integr Med 2017; 23:858-863. [PMID: 29080197 DOI: 10.1007/s11655-017-2775-3] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Indexed: 01/05/2023]
Abstract
OBJECTIVE To investigate the effect of the ethanol extract of Scutellaria barbata D. Don (EESB) on colorectal cancer (CRC) growth and Wnt/β-catenin signaling pathway in vivo and in vitro. METHODS In vivo experiment, CRC xenograft mouse model was constructed with injection of HT-29 cells. Following xenograft implantation, twenty mice were randomly divided into EESB-treated group (n=10) and control group (n=10) by a random number table, and were given with intra-gastric administration of 2 g/kg EESB or saline, 5 days a week for 16 days, respectively. At the end of experiment, tumors were removed and weighed by electronic scales. The proliferation biomarker Ki-67 of tumor was evaluated by immunohistochemistry (IHC) assay. In vitro study, HT-29 cells were treated with 0, 0.5, 1.5, 2.5 mg/mL EESB for 24 h. At the end of the treatment, the viability and survival of HT-29 cells were determined by methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay and colony formation assay, respectively. The mRNA expression of c-Myc, Survivin and adenomatous polyposis coli (APC) was examined by reverse transcription-polymerase chain reaction (RT-PCR) both in tumor tissues of CRC xenograft mice and HT-29 cells. Protein expression of c-Myc, Survivin, APC, and β-catenin as well as β-catenin phosphorylation level were evaluated by IHC assay or Western blotting. RESULTS EESB significantly reduced tumor weight in CRC xenografts mice, compared with the control group (P<0.05). IHC assay showed that EESB significantly inhibited protein expression of Ki-67 in tumor tissues (P<0.05). MTT assay showed that EESB significantly reduced HT-29 cell viability in a dose-dependent manner (P<0.05). Colony formation assay showed that EESB dose-dependently decreased the survival of HT-29 cells (P<0.05). In addition, RT-PCR assay showed that EESB decreased the mRNA expression of c-Myc and Survivin and increased APC expression, both in tumor tissues of CRC xenograft mice and HT-29 cells (P<0.05). IHC assay or Western blotting showed that EESB decreased protein expression of β-catenin, c-Myc and Survivin, as well as increased APC expression and β-catenin phosphorylation in tumor tissues or HT-29 cells (P<0.05). CONCLUSIONS EESB significantly reduced tumor growth in CRC xenografts mice, and inhibited the viability and survival of HT-29 cells. EESB could suppress the activation of the Wnt/β-catenin pathway, which might be one of the mechanisms whereby Scutellaria barbata D. Don exerts its anticancer activity.
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Affiliation(s)
- Li-Hui Wei
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Jiu-Mao Lin
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Jian-Feng Chu
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Hong-Wei Chen
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Qing-Yu Li
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
| | - Jun Peng
- Academy of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China.
- Fujian Key Laboratory of Integrative Medicine on Geriatrics, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China.
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Sadeghi MR, Jeddi F, Soozangar N, Somi MH, Samadi N. The role of Nrf2-Keap1 axis in colorectal cancer, progression, and chemoresistance. Tumour Biol 2017. [PMID: 28621229 DOI: 10.1177/1010428317705510] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is the third common cancer after lung and genital cancers worldwide with more than 1.2 million new cases diagnosed annually. Although extensive progress has been made in the treatment of colorectal cancer, finding novel targets for early diagnosis and effective treatment of these patients is an urgent need. Nuclear factor-erythroid 2-kelch-like ECH-associated protein 1 signaling pathway plays a key role in protecting cells from the damage of intracellular oxidative stress and extracellular oxidizing agents. Nuclear factor-erythroid 2 is a transcription factor that creates intracellular redox homeostasis via transcriptional activity and interaction with kelch-like ECH-associated protein 1. Furthermore, it contributes to survival and chemoresistance of colorectal cancer cells which is mediated by overexpression of cytoprotective and multidrug resistance genes. In this review, the dual role of nuclear factor-erythroid 2 signaling in induction of colorectal cancer cell survival and death as well as the possibility of targeting nuclear factor-erythroid 2-kelch-like ECH-associated protein 1 axis as an advanced strategy in prevention and effective treatment of colorectal cancer patients have been discussed.
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Affiliation(s)
- Mohammad Reza Sadeghi
- 1 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 2 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- 3 Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farhad Jeddi
- 1 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 2 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Narges Soozangar
- 1 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 2 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Hossein Somi
- 1 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Nasser Samadi
- 1 Liver and Gastrointestinal Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
- 2 Department of Molecular Medicine, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
- 4 Department of Biochemistry and Clinical Laboratories, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
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49
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Wang B, Yang J, Li S, Lv M, Chen Z, Li E, Yi M, Yang J. Tumor location as a novel high risk parameter for stage II colorectal cancers. PLoS One 2017. [PMID: 28644878 PMCID: PMC5482466 DOI: 10.1371/journal.pone.0179910] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023] Open
Abstract
Current studies do not accurately evaluate the influence of tumor location on survival of colorectal cancer patients. This study aimed to explore whether tumor location could be identified as another high-risk factor in stage II colorectal cancer by using data identified from the Surveillance, Epidemiology, and End Results database. All colorectal cancer patients between 2004 and 2008 were grouped into three according to tumor location. Of 33,789 patients diagnosed with stage II colorectal cancer, 46.8% were right colon cancer, 37.5% were left colon cancer and 15.7% were rectal cancer. The 5-year cancer specific survivals were examined. Right colon cancer was associated with the female sex, older age (> 50), and having over 12 lymph nodes resected. Conversely, rectal cancer was associated with the male sex, patients younger than 50 years of age and insufficient lymph node resection. The characteristics of left colon cancer were between them and associated with Asian or Pacific Islander populations, T4 stage, and Grade II patients. The prognostic differences between three groups were significant and retained after stratification by T stage, histological grade, number of regional nodes dissected, age at diagnose, race and sex. Furthermore, the significant difference of location was retained as an independent high-risk parameter. Thus, stage II colorectal cancers of different locations have different clinic-pathological features and cancer-specific survivals, and tumor location should be recognized as another high-risk parameter in stage II colorectal cancer.
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Affiliation(s)
- Biyuan Wang
- Department of 1Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
| | - Jiao Yang
- Department of 1Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
| | - Shuting Li
- Department of 1Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
| | - Meng Lv
- Department of 1Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
| | - Zheling Chen
- Department of 1Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
| | - Enxiao Li
- Department of 1Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
| | - Min Yi
- Breast Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Jin Yang
- Department of 1Medical Oncology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi Province, China
- * E-mail:
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50
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Pérez-Báez W, García-Latorre EA, Maldonado-Martínez HA, Coronado-Martínez I, Flores-García L, Taja-Chayeb L. Impact of fixation artifacts and threshold selection on high resolution melting analysis for KRAS mutation screening. Mol Cell Probes 2017. [PMID: 28627450 DOI: 10.1016/j.mcp.2017.06.003] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Treatment in metastatic colorectal cancer (mCRC) has expanded with monoclonal antibodies targeting epidermal growth factor receptor, but is restricted to patients with a wild-type (WT) KRAS mutational status. The most sensitive assays for KRAS mutation detection in formalin-fixed paraffin embedded (FFPE) tissues are based on real-time PCR. Among them, high resolution melting analysis (HRMA), is a simple, fast, highly sensitive, specific and cost-effective method, proposed as adjunct for KRAS mutation detection. However the method to categorize WT vs mutant sequences in HRMA is not clearly specified in available studies, besides the impact of FFPE artifacts on HRMA performance hasn't been addressed either. METHODS Avowedly adequate samples from 104 consecutive mCRC patients were tested for KRAS mutations by Therascreen™ (FDA Validated test), HRMA, and HRMA with UDG pre-treatment to reverse FFPE fixation artifacts. Comparisons of KRAS status allocation among the three methods were done. Focusing on HRMA as screening test, ROC curve analyses were performed for HRMA and HMRA-UDG against Therascreen™, in order to evaluate their discriminative power and to determine the threshold of profile concordance between WT control and sample for KRAS status determination. RESULTS Comparing HRMA and HRMA-UDG against Therascreen™ as surrogate gold standard, sensitivity was 1 for both HRMA and HRMA-UDG; and specificity and positive predictive values were respectively 0.838 and 0.939; and 0.777 and 0.913. As evaluated by the McNemar test, HRMA-UDG allocated samples to a WT/mutated genotype in a significatively different way from HRMA (p > 0.001). On the other hand HRMA-UDG did not differ from Therascreen™ (p = 0.125). ROC-curve analysis showed a significant discriminative power for both HRMA and HRMA-UDG against Therascreen™ (respectively, AUC of 0.978, p > 0.0001, CI 95% 0.957-0.999; and AUC of 0.98, p > 0.0001, CI 95% 0.000-1.0). For HRMA as a screening tool, the best threshold (degree of concordance between sample curves and WT control) was attained at 92.14% for HRMA (specificity of 0.887), and at 92.55% for HRMA-UDG (specificity of 0.952). CONCLUSIONS HRMA is a highly sensitive method for KRAS mutation detection, with apparently adequate and statistically significant discriminative power. FFPE sample fixation artifacts have an impact on HRMA results, so for HRMA on FFPE samples pre-treatment with UDG should be strongly suggested. The choice of the threshold for melting curve concordance has also great impact on HRMA performance. A threshold of 93% or greater might be adequate if using HRMA as a screening tool. Further validation of this threshold is required.
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Affiliation(s)
- Wendy Pérez-Báez
- Immunology Department and CQB Post-graduate Program, National School of Biological Sciences, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala s/n, Colonia Santo Tomás, Delegación Miguel Hidalgo, Ciudad de México, Mexico City, CP 11340, México; Molecular Pathology and Immunopathology Department, Pathology Department, Instituto Nacional de Cancerología, San Fernando 2 piso 1, Colonia Barrio del Niño Jesús, Delegación Tlalpan, Ciudad de México, Mexico City, CP 14080, México
| | - Ethel A García-Latorre
- Immunology Department and CQB Post-graduate Program, National School of Biological Sciences, Instituto Politécnico Nacional, Prol. Carpio y Plan de Ayala s/n, Colonia Santo Tomás, Delegación Miguel Hidalgo, Ciudad de México, Mexico City, CP 11340, México.
| | - Héctor Aquiles Maldonado-Martínez
- Molecular Pathology and Immunopathology Department, Pathology Department, Instituto Nacional de Cancerología, San Fernando 2 piso 1, Colonia Barrio del Niño Jesús, Delegación Tlalpan, Ciudad de México, Mexico City, CP 14080, México
| | - Iris Coronado-Martínez
- Molecular Pathology and Immunopathology Department, Pathology Department, Instituto Nacional de Cancerología, San Fernando 2 piso 1, Colonia Barrio del Niño Jesús, Delegación Tlalpan, Ciudad de México, Mexico City, CP 14080, México
| | - Leonardo Flores-García
- Blood Bank, Instituto Nacional de Cancerología, San Fernando 22, Colonia Sección XVI, Delegación Tlalpan, Ciudad de México, Mexico City, CP 14080, México
| | - Lucía Taja-Chayeb
- Pharmacogenetics Laboratory, Instituto Nacional de Cancerología, San Fernando 22, Colonia Sección XVI, Delegación Tlalpan, Ciudad de México, Mexico City, CP 14080, México
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