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McDonald HG, Kerekes DM, Kim J, Khan SA. Precision Oncology in Gastrointestinal and Colorectal Cancer Surgery. Surg Oncol Clin N Am 2024; 33:321-341. [PMID: 38401913 DOI: 10.1016/j.soc.2023.12.007] [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: 02/26/2024]
Abstract
Precision medicine is used to treat gastrointestinal malignancies including esophageal, gastric, small bowel, colorectal, and pancreatic cancers. Cutting-edge assays to detect and treat these cancers are active areas of research and will soon become standard of care. Colorectal cancer is a prime example of precision oncology as disease site is no longer the final determinate of treatment. Here, the authors describe how leveraging an understanding of tumor biology translates to individualized patient care using evidence-based practices.
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Affiliation(s)
- Hannah G McDonald
- Department of General Surgery, Division of Surgical Oncology, The University of Kentucky, 800 Rose Street, Lexington, KY 40508, USA
| | - Daniel M Kerekes
- Department of General Surgery, Division of Surgical Oncology, Yale University, 15 York Street, New Haven, CT 06510, USA
| | - Joseph Kim
- Department of General Surgery, Division of Surgical Oncology, The University of Kentucky, 800 Rose Street, Lexington, KY 40508, USA
| | - Sajid A Khan
- Department of Surgery, Yale University, 15 York Street, New Haven, CT 06510, USA.
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Chi Y, Yuan H, Fan Q, Wang Z, Niu Z, Yu J, Yuan D. Clinical-Molecular characteristics and Post-Translational modifications of colorectal cancer in north China: Implications for future targeted therapies. Gene 2024; 899:148134. [PMID: 38185290 DOI: 10.1016/j.gene.2024.148134] [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: 09/11/2023] [Revised: 12/12/2023] [Accepted: 01/02/2024] [Indexed: 01/09/2024]
Abstract
This study delineated the elucidate molecular changes and their post-translational modifications (PTMs) in heterogenetic colorectal cancer (CRC) for a deeper understanding of the CRC pathophysiology and identifying potential therapeutic targets. In this retrospective study, the profiles of 13 hot spot gene mutations were analyzed and the microsatellite instability (MSI) status was determined.Employing the Circulating Single-Molecule Amplification and Resequencing Technology (cSMART) assay, the clinical-pathological features of CRC were characterized in 249 Chinese patients. PTMs were quantified online.Among the patients with CRC, the mutation frequencies of KRAS, NRAS, BRAF, PIK3CA, TP53, and APC genes were 47.8%, 3.6%, 4.8%, 13.7%, 55.8%, and 36.9%, respectively. The proportion of MSI-high (MSI-H) was 7.8%.Subsequent multiple logistic regression analysis showed significant associations including a link between lung metastasis and KRAS mutation, between liver metastasis and lymph node metastasis, between MSI-H and early-onset CRC (EOCRC) and KRAS mutation, between right-sided colon cancer and peritoneal metastasis, and between PIK3CA mutation and PTEN mutation. Patients with KRAS mutation presented with MSI-H, lung metastasis, and PIK3CA mutation. MSI-H, BRAF mutation, and PTEN mutation were more frequent in EOCRC. Phosphorylation and ubiquitylation were found in KRAS, BRAF, PTEN, and SMAD4; SUMOylation and ubiquitylation were observed in HRAS and NRAS; while phosphorylation was obvious in APC, P53, and MLH1. Notably, Phosphorylation and ubiquitylation were the two most common PTMs. The biological characteristics of CRC in Chinese patients have some unique clinical features, which can be explained by the genetic mutation profile, correlations among gene mutations and clinical characteristics. These distinctions set the Chinese patient population apart from their Western counterparts.
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Affiliation(s)
- Yajing Chi
- School of Medicine, Nankai University, Tianjin, China; Cancer Center, The General Hospital of the People's Liberation Army, Beijing, China
| | - Hongtu Yuan
- Department of Pathology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Qing Fan
- Department of Pharmacy, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zhendan Wang
- Department of Thoracic Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Zuoxing Niu
- Department of Gastroenterology Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Jinming Yu
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China
| | - Dandan Yuan
- Department of Gastroenterology Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
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Heregger R, Huemer F, Steiner M, Gonzalez-Martinez A, Greil R, Weiss L. Unraveling Resistance to Immunotherapy in MSI-High Colorectal Cancer. Cancers (Basel) 2023; 15:5090. [PMID: 37894457 PMCID: PMC10605634 DOI: 10.3390/cancers15205090] [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: 09/28/2023] [Revised: 10/18/2023] [Accepted: 10/19/2023] [Indexed: 10/29/2023] Open
Abstract
Colorectal cancer (CRC) is the third most common cancer and the second leading cause of cancer-related deaths. Incidences of early CRC cases are increasing annually in high-income countries, necessitating effective treatment strategies. Immune checkpoint inhibitors (ICIs) have shown significant clinical efficacy in various cancers, including CRC. However, their effectiveness in CRC is limited to patients with mismatch-repair-deficient (dMMR)/microsatellite instability high (MSI-H) disease, which accounts for about 15% of all localized CRC cases and only 3% to 5% of metastatic CRC cases. However, the varied response among patients, with some showing resistance or primary tumor progression, highlights the need for a deeper understanding of the underlying mechanisms. Elements involved in shaping the response to ICIs, such as tumor microenvironment, immune cells, genetic changes, and the influence of gut microbiota, are not fully understood thus far. This review aims to explore potential resistance or immune-evasion mechanisms to ICIs in dMMR/MSI-H CRC and the cell types involved, as well as possible pitfalls in the diagnosis of this particular subtype.
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Affiliation(s)
- Ronald Heregger
- Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University, 5020 Salzburg, Austria (F.H.); (M.S.)
| | - Florian Huemer
- Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University, 5020 Salzburg, Austria (F.H.); (M.S.)
| | - Markus Steiner
- Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University, 5020 Salzburg, Austria (F.H.); (M.S.)
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
| | - Alejandra Gonzalez-Martinez
- Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University, 5020 Salzburg, Austria (F.H.); (M.S.)
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
| | - Richard Greil
- Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University, 5020 Salzburg, Austria (F.H.); (M.S.)
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
| | - Lukas Weiss
- Department of Internal Medicine III with Hematology, Medical Oncology, Hemostaseology, Infectiology and Rheumatology, Oncologic Center, Salzburg Cancer Research Institute-Laboratory for Immunological and Molecular Cancer Research (SCRI-LIMCR), Center for Clinical Cancer and Immunology Trials (CCCIT), Paracelsus Medical University, 5020 Salzburg, Austria (F.H.); (M.S.)
- Cancer Cluster Salzburg, 5020 Salzburg, Austria
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Na W, Lee IJ, Koh I, Kwon M, Song YS, Lee SH. Cancer-specific functional profiling in microsatellite-unstable (MSI) colon and endometrial cancers using combined differentially expressed genes and biclustering analysis. Medicine (Baltimore) 2023; 102:e33647. [PMID: 37171359 PMCID: PMC10174364 DOI: 10.1097/md.0000000000033647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 05/13/2023] Open
Abstract
Microsatellite-unstable (MSI) cancers have distinct genetic and clinical features from microsatellite-stable cancers, but the molecular functional differences between MSI cancers originating from different tissues or organs have not been well studied because the application of usual differentially expressed gene (DEG) analysis is error-prone, producing too many noncancer-specific normally functioning genes. To maximize therapeutic efficacy, biomarkers reflecting cancer-specific differences between MSI cancers of different tissue origins should be identified. To identify functional differences between MSI colon and endometrial cancers, we combined DEG analysis and biclustering instead of DEG analysis alone and refined functionally relevant biclusters reflecting genuine functional differences between the 2 tumors. Specifically, using The Cancer Genome Atlas and genome-tissue expression as data sources, gene ontology (GO) enrichment tests were performed after routinely identifying DEGs between the 2 tumors with the exclusion of DEGs identified in their normal counterparts. Cancer-specific biclusters and associated enriched GO terms were obtained by biclustering with enrichment tests for the preferences for cancer type (either colon or endometrium) and GO enrichment tests for each cancer-specific bicluster, respectively. A novel childness score was developed to select functionally relevant biclusters among cancer-specific biclusters based on the extent to which the enriched GO terms of the biclusters tended to be child terms of the enriched GO terms in DEGs. The selected biclusters were tested using survival analysis to validate their clinical significance. We performed multiple sequential analyses to produce functionally relevant biclusters from the RNA sequencing data of MSI colon and endometrial cancer samples and their normal counterparts. We identified 3066 cancer-specific DEGs. Biclustering analysis revealed 153 biclusters and 41 cancer-specific biclusters were selected using Fisher exact test. A mean childness score over 0.6 was applied as the threshold and yielded 8 functionally relevant biclusters from cancer-specific biclusters. Functional differences appear to include gland cavitation and the TGF-β receptor, G protein, and cytokine pathways. In the survival analysis, 6 of the 8 functionally relevant biclusters were statistically significant. By attenuating noise and applying a synergistic contribution of DEG results, we refined candidate biomarkers to complement tissue-specific features of MSI tumors.
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Affiliation(s)
- Woong Na
- Department of Pathology, H Plus Yangji Hospital, Seoul, South Korea
- Department of Pathology, College of Medicine, Hanyang University, Seoul, South Korea
| | - Il Ju Lee
- Department of Biomedical Informatics, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul, South Korea
| | - Insong Koh
- Department of Biomedical Informatics, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul, South Korea
| | - Mihye Kwon
- Department of Internal Medicine, College of Medicine, Konyang University, Daejeon, South Korea
| | - Young Soo Song
- Department of Pathology, College of Medicine, Konyang University, Daejeon, South Korea
| | - Sung Hak Lee
- Department of Pathology, College of Medicine, Catholic University, Seoul, South Korea
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Han S, Chok AY, Peh DYY, Ho JZM, Tan EKW, Koo SL, Tan IBH, Ong JCA. The distinct clinical trajectory, metastatic sites, and immunobiology of microsatellite-instability-high cancers. Front Genet 2022; 13:933475. [DOI: 10.3389/fgene.2022.933475] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Accepted: 10/17/2022] [Indexed: 12/03/2022] Open
Abstract
Microsatellite-instability-high (MSI-H) cancers form a spectrum of solid organ tumors collectively known as Lynch Syndrome cancers, occurring not only in a subset of colorectal, endometrial, small bowel, gastric, pancreatic, and biliary tract cancers but also in prostate, breast, bladder, and thyroid cancers. Patients with Lynch Syndrome harbor germline mutations in mismatch repair genes, with a high degree of genomic instability, leading to somatic hypermutations and, therefore, oncogenesis and cancer progression. MSI-H cancers have unique clinicopathological characteristics compared to their microsatellite-stable (MSS) counterparts, marked by a higher neoantigen load, immune cell infiltration, and a marked clinical response to immune checkpoint blockade. Patients with known Lynch Syndrome may be detected early through surveillance, but some patients present with disseminated metastatic disease. The treatment landscape of MSI-H cancers, especially colorectal cancers, has undergone a paradigm shift and remains to be defined, with immune checkpoint blockade coming to the forefront of treatment strategies in the stage IV setting. We summarize in this review the clinical features of MSI-H cancers with a specific interest in the pattern of spread or recurrence, disease trajectory, and treatment strategies. We also summarize the tumor-immune landscape and genomic profile of MSI-H cancers and potential novel therapeutic strategies.
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Association of β-Catenin, APC, SMAD3/4, Tp53, and Cyclin D1 Genes in Colorectal Cancer: A Systematic Review and Meta-Analysis. Genet Res (Camb) 2022; 2022:5338956. [PMID: 36072013 PMCID: PMC9402361 DOI: 10.1155/2022/5338956] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Accepted: 06/27/2022] [Indexed: 11/25/2022] Open
Abstract
Objectives Accumulating evidence indicates that the expression and/or variants of several genes play an essential role in the progress of colorectal cancer (CRC). The current study is a meta-analysis undertaken to estimate the prognosis and survival associated with CTNNB1/β-catenin, APC, Wnt, SMAD3/4, TP53, and Cyclin D1 genes among CRC patients. Methods The authors searched PubMed, EMBASE, and Science Direct for relevant reports published between 2000 and 2020 and analyzed them to determine any relationship between the (immunohistochemically/sequencing-detected) gene expression and variants of the selected genes and the survival of CRC patients. Results The analysis included 34,074 patients from 64 studies. To evaluate association, hazard ratios (HRs) were estimated for overall survival (OS) or disease-free survival (DFS), with a 95% confidence interval (CIs). Pooled results showed that β-catenin overexpression, APC mutation, SMAD-3 or 4 loss of expression, TP53 mutations, and Cyclin D1 expression were associated with shorter OS. β-Catenin overexpression (HR: 0.137 (95% CI: 0.131–0.406)), loss of expression of SMAD3 or 4 (HR: 0.449 (95% CI: 0.146–0.753)), the mutations of TP53 (HR: 0.179 (95% CI: 0.126–0.485)), and Cyclin D1 expression (HR: 0.485 (95% CI: 0.772–0.198)) also presented risk for shorter DFS. Conclusions The present meta-analysis indicates that overexpression or underexpression and variants of CTNNB1/β-catenin, APC, SMAD3/4, TP53, and Cyclin D1 genes potentially acted as unfavorable biomarkers for the prognosis of CRC. The Wnt gene was not associated with prognosis.
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Zheng Y, Qin Y, Gong W, Li H, Li B, Wang Y, Chao B, Zhao S, Liu L, Yao S, Shi J, Shi X, Wang K, Xu S. Specific genomic alterations and prognostic analysis of perihilar cholangiocarcinoma and distal cholangiocarcinoma. J Gastrointest Oncol 2021; 12:2631-2642. [PMID: 35070393 PMCID: PMC8748027 DOI: 10.21037/jgo-21-776] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 12/16/2021] [Indexed: 11/15/2023] Open
Abstract
BACKGROUND Cholangiocarcinoma (CCA), which consists of intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), is an aggressive malignancy worldwide. PCCA and dCCA are often classified as extrahepatic CCA (exCCA). However, the differences in mutational characteristics between pCCA and dCCA remain unclear. METHODS Deep sequencing targeting of 450 cancer genes was performed for genomic alteration detection. The tumor mutational burden (TMB) was measured by an algorithm developed in-house. Correlation analysis was conducted using Fisher's exact test. RESULTS FGFR2 and ERBB2 mutations mainly occurred in iCCA and exCCA, respectively. In exCCA, the frequencies of PIK3CA, FAT4, KDM6A, MDM2, and TCF7L2 mutations were significantly higher in pCCA compared to dCCA, while the frequencies of TP53 and KRAS mutations were markedly lower in pCCA than those in dCCA. The prognosis-related mutations were different among the CCA subtypes. NF1 mutation was associated with short disease-free survival (DFS) and overall survival (OS), and ERBB2 mutation was associated with short DFS in dCCA patients. Meanwhile, MAP2K4 mutation was associated with long DFS and OS, and TERT mutation was associated with short DFS in pCCA. A series of mutations in genes, including ARID1A, ARID2, SMAD4, TERT, TP53, and KRAS, were found to be associated with the TMB. CONCLUSIONS In this study, we investigated the comprehensive genomic characterizations of CCA patients, identified the significant alterations in each subtype, and identified potential biomarkers for prognosis prediction. These results provide molecular evidence for the heterogeneity of CCA subtypes and evidence for further precision targeted therapy of CCA patients.
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Affiliation(s)
- Yuanwen Zheng
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- School of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Yejun Qin
- Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Wei Gong
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Hongguang Li
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Bin Li
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Yu Wang
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Baoting Chao
- School of Clinical Medicine, Cheeloo College of Medicine, Shandong University, Jinan, China
| | - Shulei Zhao
- Department of Gastroenterology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Luguang Liu
- Department of Gastrointestinal Surgery, Cancer Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Shuzhan Yao
- Department of Medical Imaging, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Junping Shi
- Shanghai OrigiMed Co., Ltd., Shanghai, China
| | | | - Kai Wang
- Shanghai OrigiMed Co., Ltd., Shanghai, China
| | - Shifeng Xu
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
- Department of Hepatobiliary Surgery, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, China
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Ouahoud S, Jacobs RJ, Kodach LL, Voorneveld PW, Hawinkels LJAC, Weil NL, van Vliet B, Herings RM, van der Burg LRA, van Wezel T, Morreau H, Slingerland M, Bastiaannet E, Putter H, Hardwick JCH. Statin use is associated with a reduced incidence of colorectal cancer expressing SMAD4. Br J Cancer 2021; 126:297-301. [PMID: 34703008 DOI: 10.1038/s41416-021-01604-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2021] [Revised: 09/20/2021] [Accepted: 10/13/2021] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Long-term use of statins is associated with a small reduced risk of colorectal cancer but their mechanism of action is not well understood. While they are generally believed to act on KRAS, we have previously proposed that they act via influencing the BMP pathway. The objective of this study was to look for associations between statin use and the risk of developing colorectal cancer of a particular molecular subtype. METHODS By linking two registries unique to the Netherlands, 69,272 statin users and 94,753 controls were identified and, if they developed colorectal cancer, their specimens traced. Colorectal cancers were molecularly subtyped according to the expression of SMAD4 and the mutation status of KRAS and BRAF. RESULTS Statin use was associated with a reduction in the risk of developing colorectal cancer regardless of molecular subtype (HR 0.77; 95% CI 0.66-0.89) and a larger reduction in the risk of developing SMAD4-positive colorectal cancer (OR 0.64; 95% CI 0.42-0.82). There was no relationship between statin use and the risk of developing colorectal cancer with a mutation in KRAS and/or BRAF. CONCLUSIONS Statin use is associated with a reduced risk of developing colorectal cancer with intact SMAD4 expression.
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Affiliation(s)
- Sarah Ouahoud
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Utrecht, The Netherlands
| | - Rutger J Jacobs
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Utrecht, The Netherlands
| | - Ludmilla L Kodach
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Utrecht, The Netherlands
| | - Philip W Voorneveld
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Utrecht, The Netherlands
| | - Lukas J A C Hawinkels
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Utrecht, The Netherlands
| | - Nikki L Weil
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Utrecht, The Netherlands
| | - Britt van Vliet
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Utrecht, The Netherlands
| | - Ron M Herings
- PHARMO Institute for Drug Outcomes Research, Utrecht, The Netherlands.,Department of Epidemiology & Data Science, Utrecht, The Netherlands
| | - Lennart R A van der Burg
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Utrecht, The Netherlands
| | - Tom van Wezel
- Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Hans Morreau
- Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Marije Slingerland
- Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Esther Bastiaannet
- Department of Medical Oncology, Leiden University Medical Centre, Leiden, The Netherlands.,Department of Surgery, Leiden University Medical Centre, Leiden, The Netherlands
| | - Hein Putter
- Department of Medical Statistics, Leiden University Medical Centre, Leiden, The Netherlands
| | - James C H Hardwick
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Utrecht, The Netherlands.
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Fang T, Liang T, Wang Y, Wu H, Liu S, Xie L, Liang J, Wang C, Tan Y. Prognostic role and clinicopathological features of SMAD4 gene mutation in colorectal cancer: a systematic review and meta-analysis. BMC Gastroenterol 2021; 21:297. [PMID: 34301194 PMCID: PMC8299661 DOI: 10.1186/s12876-021-01864-9] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 06/21/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Approximately 5.0-24.2% of colorectal cancers (CRCs) have inactivating mutations in SMAD4, making it one of the frequently mutated genes in CRC. We thus carried out a comprehensive system review and meta-analysis investigating the prognostic significance and clinicopathological features of SMAD4 gene mutation in CRC patients. METHODS A detailed literature search was conducted in PubMed, Web of Science and Embase databases to study the relationship between SMAD4 mutations and the demographic and clinicopathological characteristics in CRC patients. The hazard ratios (HRs) with 95% confidence intervals (CI) were used to evaluate the effect of SMAD4 mutations on overall survival (OS) and progression-free survival (PFS)/recurrence-free survival (RFS). RESULTS Ten studies enrolling 4394 patients were eligible for inclusion. Data on OS were available from 5 studies and data on PFS/RFS were available from 3 studies. Comparing SMAD4-mutated CRC patients with SMAD4 wild-type CRC patients, the summary HR for OS was 1.46 (95% CI 1.28-1.67, P = 0.001), the summary HR for PFS/RFS was 1.59 (95% CI 1.14-2.22, P = 0.006). In terms of clinicopathology parameters, 9 studies have data that can be extracted, SMAD4 mutations were associated with tumor location (odds ratio [OR] = 1.15, colon/rectum, 95% CI 1.01-1.31, P = 0.042), TNM stage (OR = 1.28, stage IV/I-III, 95% CI 1.03-1.58, P = 0.025), lymph node metastasis (OR = 1.42, N1 + N2/N0, 95% CI 1.20-1.67, P < 0.001), mucinous differentiation (OR = 2.23, 95% CI 1.85-2.70, P < 0.001) and rat sarcoma viral oncogene homolog (RAS) mutation status (OR = 2.13, 95% CI 1.37-3.34, P = 0.001). No connection was found with age, gender, tumor grade, microsatellite instability status and b-viral oncogene homolog B1 mutation status. Besides, publication bias was not observed in any study. CONCLUSIONS This meta-analysis suggests that SMAD4 mutation was associated with OS, PFS/RFS, and clinicopathological parameters, including tumor site, disease stage, RAS status, lymph node metastasis and mucinous differentiation. Our meta-analysis indicated that SMAD4 mutations could predict the poor prognosis and aggressive clinicopathological characteristics of CRC. More large-sample cohort studies are needed to confirm this conclusion. Since SMAD4 mutations are closely related to RAS mutations, their relationship warrants further investigation.
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Affiliation(s)
- Tian Fang
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Tingting Liang
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Yizhuo Wang
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Haitao Wu
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Shuhan Liu
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Linying Xie
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Jiaying Liang
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China
| | - Chang Wang
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China.
| | - Yehui Tan
- Cancer Center, The First Hospital of Jilin University, No. 1 Xinmin Street, Changchun, 130021, Jilin Province, China.
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Dai ZT, Wang J, Zhao K, Xiang Y, Li JP, Zhang HM, Peng ZT, Liao XH. Integrated TCGA and GEO analysis showed that SMAD7 is an independent prognostic factor for lung adenocarcinoma. Medicine (Baltimore) 2020; 99:e22861. [PMID: 33126329 PMCID: PMC7598801 DOI: 10.1097/md.0000000000022861] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
The lack of effective markers leads to missed optimal treatment times, resulting in poorer prognosis in most cancers. Drosophila mothers against decapentaplegic protein (SMAD) family members are important cytokines in the transforming growth factor-beta family. They jointly regulate the processes of cell growth, differentiation, and apoptosis. However, the expression of SMAD family genes in pan-cancers and their impact on prognosis have not been elucidated. Perl software and R software were used to perform expression analysis and survival curve analysis on the data collected by TCGA, GTEx, and GEO, and the potential regulatory pathways were determined through gene ontology enrichment and kyoto encyclopedia of genes and genomes enrichment analysis. It was found that SMAD7 and SMAD9 expression decreased in lung adenocarcinoma (LUAD), and their expression was positively correlated with survival time. Additionally, SMAD7 could be used as an independent prognostic factor for LUAD. In general, SMAD7 and SMAD9 can be used as prognostic markers of LUAD. Further, SMAD7 is expected to become a therapeutic target for LUAD.
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Affiliation(s)
- Zhou-Tong Dai
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan
| | - Jun Wang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan
| | - Kai Zhao
- Huangshi Central Hospital, Huangshi
| | | | - Jia Peng Li
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan
| | - Hui-Min Zhang
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan
| | - Zi-Tan Peng
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan
- Hebei Kingsci Pharmaceutical Technology Co., Ltd, Shijiazhuang, Hebei, P.R. China
| | - Xing Hua Liao
- Institute of Biology and Medicine, College of Life and Health Sciences, Wuhan University of Science and Technology, Wuhan
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11
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Mohd Yunos RI, Ab Mutalib NS, Tieng FYF, Abu N, Jamal R. Actionable Potentials of Less Frequently Mutated Genes in Colorectal Cancer and Their Roles in Precision Medicine. Biomolecules 2020; 10:biom10030476. [PMID: 32245111 PMCID: PMC7175115 DOI: 10.3390/biom10030476] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 02/06/2023] Open
Abstract
Global statistics have placed colorectal cancer (CRC) as the third most frequently diagnosed cancer and the fourth principal cause of cancer-related deaths worldwide. Improving survival for CRC is as important as early detection. Personalized medicine is important in maximizing an individual's treatment success and minimizing the risk of adverse reactions. Approaches in achieving personalized therapy in CRC have included analyses of specific genes with its clinical implications. Tumour genotyping via next-generation sequencing has become a standard practice to guide clinicians into predicting tumor behaviour, disease prognosis, and treatment response. Nevertheless, better prognostic markers are necessary to further stratify patients for personalized treatment plans. The discovery of new markers remains indispensable in providing the most effective chemotherapy in order to improve the outcomes of treatment and survival in CRC patients. This review aims to compile and discuss newly discovered, less frequently mutated genes in CRC. We also discuss how these mutations are being used to assist therapeutic decisions and their potential prospective clinical utilities. In addition, we will summarize the importance of profiling the large genomic rearrangements, gene amplification, and large deletions and how these alterations may assist in determining the best treatment option for CRC patients.
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Affiliation(s)
| | | | | | | | - Rahman Jamal
- Correspondence: (N.S.A.M.); (R.J.); Tel.: +60-3-91459073 (N.S.A.M.); +60-3-91459000 (R.J.)
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12
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Gu S, Zaidi S, Hassan I, Mohammad T, Malta TM, Noushmehr H, Nguyen B, Crandall KA, Srivastav J, Obias V, Lin P, Nguyen BN, Yao M, Yao R, King CH, Mazumder R, Mishra B, Rao S, Mishra L. Mutated CEACAMs Disrupt Transforming Growth Factor Beta Signaling and Alter the Intestinal Microbiome to Promote Colorectal Carcinogenesis. Gastroenterology 2020; 158:238-252. [PMID: 31585122 PMCID: PMC7124154 DOI: 10.1053/j.gastro.2019.09.023] [Citation(s) in RCA: 48] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2019] [Revised: 09/17/2019] [Accepted: 09/20/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND & AIMS We studied interactions among proteins of the carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, which interact with microbes, and transforming growth factor beta (TGFB) signaling pathway, which is often altered in colorectal cancer cells. We investigated mechanisms by which CEACAM proteins inhibit TGFB signaling and alter the intestinal microbiome to promote colorectal carcinogenesis. METHODS We collected data on DNA sequences, messenger RNA expression levels, and patient survival times from 456 colorectal adenocarcinoma cases, and a separate set of 594 samples of colorectal adenocarcinomas, in The Cancer Genome Atlas. We performed shotgun metagenomic sequencing analyses of feces from wild-type mice and mice with defects in TGFB signaling (Sptbn1+/- and Smad4+/-/Sptbn1+/-) to identify changes in microbiota composition before development of colon tumors. CEACAM protein and its mutants were overexpressed in SW480 and HCT116 colorectal cancer cell lines, which were analyzed by immunoblotting and proliferation and colony formation assays. RESULTS In colorectal adenocarcinomas, high expression levels of genes encoding CEACAM proteins, especially CEACAM5, were associated with reduced survival times of patients. There was an inverse correlation between expression of CEACAM genes and expression of TGFB pathway genes (TGFBR1, TGFBR2, and SMAD3). In colorectal adenocarcinomas, we also found an inverse correlation between expression of genes in the TGFB signaling pathway and genes that regulate stem cell features of cells. We found mutations encoding L640I and A643T in the B3 domain of human CEACAM5 in colorectal adenocarcinomas; structural studies indicated that these mutations would alter the interaction between CEACAM5 and TGFBR1. Overexpression of these mutants in SW480 and HCT116 colorectal cancer cell lines increased their anchorage-independent growth and inhibited TGFB signaling to a greater extent than overexpression of wild-type CEACAM5, indicating that they are gain-of-function mutations. Compared with feces from wild-type mice, feces from mice with defects in TGFB signaling had increased abundance of bacterial species that have been associated with the development of colon tumors, including Clostridium septicum, and decreased amounts of beneficial bacteria, such as Bacteroides vulgatus and Parabacteroides distasonis. CONCLUSION We found expression of CEACAMs and genes that regulate stem cell features of cells to be increased in colorectal adenocarcinomas and inversely correlated with expression of TGFB pathway genes. We found colorectal adenocarcinomas to express mutant forms of CEACAM5 that inhibit TGFB signaling and increase proliferation and colony formation. We propose that CEACAM proteins disrupt TGFB signaling, which alters the composition of the intestinal microbiome to promote colorectal carcinogenesis.
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Affiliation(s)
- Shoujun Gu
- Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, DC, USA
| | - Sobia Zaidi
- Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, DC, USA
| | - Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, India
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, India
| | - Tathiane M. Malta
- Department of Neurosurgery, Henry Ford Health System, Detroit, MI, USA
| | - Houtan Noushmehr
- Department of Neurosurgery, Henry Ford Health System, Detroit, MI, USA
| | - Bryan Nguyen
- Computational Biology Institute and Department of Biostatistics & Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA
| | - Keith A. Crandall
- Computational Biology Institute and Department of Biostatistics & Bioinformatics, Milken Institute School of Public Health, The George Washington University, Washington, DC, USA
| | | | - Vincent Obias
- Department of Surgery, The George Washington University, Washington, DC, USA
| | - Paul Lin
- Department of Surgery, The George Washington University, Washington, DC, USA
| | - Bao-Ngoc Nguyen
- Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, DC, USA
| | - Michael Yao
- Department of Gastroenterology, Veterans Affairs Medical Center, Washington DC, USA
| | - Ren Yao
- Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC, USA
| | - Charles Hadley King
- Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC, USA
| | - Raja Mazumder
- Department of Biochemistry and Molecular Medicine, The George Washington University, Washington, DC, USA
| | - Bibhuti Mishra
- Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, DC, USA
| | - Shuyun Rao
- Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, DC, USA
| | - Lopa Mishra
- Center for Translational Medicine, Department of Surgery, The George Washington University, Washington, DC, USA
- Department of Gastroenterology, Veterans Affairs Medical Center, Washington DC, USA
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13
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Advani SM, Advani PS, Brown DW, DeSantis SM, Korphaisarn K, VonVille HM, Bressler J, Lopez DS, Davis JS, Daniel CR, Sarshekeh AM, Braithwaite D, Swartz MD, Kopetz S. Global differences in the prevalence of the CpG island methylator phenotype of colorectal cancer. BMC Cancer 2019; 19:964. [PMID: 31623592 PMCID: PMC6796359 DOI: 10.1186/s12885-019-6144-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Accepted: 09/10/2019] [Indexed: 02/07/2023] Open
Abstract
Background CpG Island Methylator Phenotype (CIMP) is an epigenetic phenotype in CRC characterized by hypermethylation of CpG islands in promoter regions of tumor suppressor genes, leading to their transcriptional silencing and loss of function. While the prevalence of CRC differs across geographical regions, no studies have compared prevalence of CIMP-High phenotype across regions. The purpose of this project was to compare the prevalence of CIMP across geographical regions after adjusting for variations in methodologies to measure CIMP in a meta-analysis. Methods We searched PubMed, Medline, and Embase for articles focusing on CIMP published from 2000 to 2018. Two reviewers independently identified 111 articles to be included in final meta-analysis. We classified methods used to quantify CIMP into 4 categories: a) Classical (MINT marker) Panel group b) Weisenberg-Ogino (W-O) group c) Human Methylation Arrays group and d) Miscellaneous group. We compared the prevalence of CIMP across geographical regions after correcting for methodological variations using meta-regression techniques. Results The pooled prevalence of CIMP-High across all studies was 22% (95% confidence interval:21–24%; I2 = 94.75%). Pooled prevalence of CIMP-H across Asia, Australia, Europe, North America and South America was 22, 21, 21, 27 and 25%, respectively. Meta-regression analysis identified no significant differences in the prevalence of CIMP-H across geographical regions after correction for methodological variations. In exploratory analysis, we observed variations in CIMP-H prevalence across countries. Conclusion Although no differences were found for CIMP-H prevalence across countries, further studies are needed to compare the influence of demographic, lifestyle and environmental factors in relation to the prevalence of CIMP across geographical regions.
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Affiliation(s)
- Shailesh Mahesh Advani
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA. .,Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20007, USA. .,Social Behavioral Research Branch, National Human Genome Research Institute, National Institute of Health, Bethesda, MD, 20892, USA.
| | - Pragati Shailesh Advani
- Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Institutes of Health, National Cancer Institute, Rockville, MD, 20850, USA
| | - Derek W Brown
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Stacia M DeSantis
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Krittiya Korphaisarn
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA
| | - Helena M VonVille
- Library, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Jan Bressler
- Department of Epidemiology, Human Genetics and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - David S Lopez
- Division of Urology- UTHealth McGovern Medical School, Houston, TX, 77030, USA.,Department of Preventive Medicine and Community Health, UTMB Health-School of Medicine, Galveston, TX, 77555-1153, USA
| | - Jennifer S Davis
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Carrie R Daniel
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Amir Mehrvarz Sarshekeh
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA
| | - Dejana Braithwaite
- Cancer Prevention and Control Program, Lombardi Comprehensive Cancer Center, Georgetown University, Washington DC, 20007, USA
| | - Michael D Swartz
- Department of Biostatistics and Data Science, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Scott Kopetz
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Unit 0426, Houston, TX, 77030, USA.
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14
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Kim H, Kim BH, Lee D, Shin E. Genomic alterations in signet ring and mucinous patterned colorectal carcinoma. Pathol Res Pract 2019; 215:152566. [PMID: 31400926 DOI: 10.1016/j.prp.2019.152566] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2019] [Revised: 07/10/2019] [Accepted: 07/26/2019] [Indexed: 02/07/2023]
Abstract
BACKGROUND The genetic alterations (GAs) in two specific histological subtypes of colorectal cancer (CRC), signet ring cell colorectal carcinoma (SRC) and mucinous colorectal carcinoma (MC), are not well known. In the present study, we employed next-generation sequencing to perform genetic profiling of SRC and MC, and compared the spectrum of GAs with the alterations found in conventional type colorectal cancer (CON). MATERIALS AND METHODS We selected 46 CRCs comprising 17 SRCs and mucinous carcinoma with signet ring cell component (SRCCs), 17 MCs, and 12 CONs with microsatellite stability or microsatellite instability-low. Deep sequencing was performed using a targeted cancer panel composed of 171 cancer-related genes. SMAD4 protein expression was evaluated by immunohistochemical staining. RESULTS We detected 108 mutations in 18 different genes. Overall, 2.34 GAs were detected per tumor (range, 0-14). The overall frequency of GA and alteration in targetable genes was less prevalent in SRC/SRCC compared to the frequency of alteration in MC/CON (p = 0.040 and p < 0.001, respectively). The GA profile of SRC/SRCC included TP53 (8/17, 47.1%), SMAD4 (5/17, 29.4%), KRAS (4/17.23.5%), APC (4/17.23.5%), PIK3CA, ATM, BRAF, and PIK3R1 (1/17, 5.9%, each). KRAS mutation was significantly less prevalent in SRC/SRCC compared to the number of KRAS mutations in MC (12/17, 70.6%) and CON (9/12, 75.0%) (p = 0.015 and 0.01, respectively). Compared to the 152 non-hypermutated CONs from TCGA database, SMAD4 alteration was predominant in SRC/SRCC (p = 0.045) with aberrant loss of SMAD4 expression (13/17, 76.5%) compared to the SMAD4 alterations in CON (5/15, 33.3%) (p = 0.031). Accordingly, KRAS (12/17, 70.6%), APC (6/17, 35.3%), SMAD4, TP53 (4/17, 23.5%, each), PIK3CA (3/17, 17.6%), AKT1, ATM, BRAF, EGFR, and EZH2 (1/17, 5.9%, each) were altered in MC. APC and TP53 mutations were less frequent in MC compared to those in TCGA-CON (p < 0.001 and 0.003, respectively) whereas KRAS mutation was prevalent (p = 0.041). CONCLUSION Alterations of known cancer associated genes and targetable genes in SRC/SRCC are infrequent. The profile of GAs in SRC/SRCC and MC differs from the GA profile of CON. Specifically, SMAD4 mutation and loss of SMAD4 expression is frequently found in SRC/SRCC. The genetic profiles revealed in the present study may aid in developing precision medicine for CRC treatment based on histological subtype.
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Affiliation(s)
- Hyunchul Kim
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Gyeonggi, South Korea
| | - Bo-Hyung Kim
- Department of Clinical Pharmacology and Therapeutics, Kyung Hee University College of Medicine and Hospital, Seoul, South Korea
| | - Donghwan Lee
- Department of Statistics, Ewha Womans University, Seoul, South Korea
| | - Eun Shin
- Department of Pathology, Hallym University Dongtan Sacred Heart Hospital, Hwaseong, Gyeonggi, South Korea; Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Gyeonggi, South Korea.
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15
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Yoo SY, Lee JA, Shin Y, Cho NY, Bae JM, Kang GH. Clinicopathological Characterization and Prognostic Implication of SMAD4 Expression in Colorectal Carcinoma. J Pathol Transl Med 2019; 53:289-297. [PMID: 31237997 PMCID: PMC6755646 DOI: 10.4132/jptm.2019.06.07] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Accepted: 06/07/2019] [Indexed: 12/24/2022] Open
Abstract
Background SMAD family member 4 (SMAD4) has gained attention as a promising prognostic factor of colorectal cancer (CRC) as well as a key molecule to understand the tumorigenesis and progression of CRC. Methods We retrospectively analyzed 1,281 CRC cases immunohistochemically for their expression status of SMAD4, and correlated this status with clinicopathologic and molecular features of CRCs. Results A loss of nuclear SMAD4 was significantly associated with frequent lymphovascular and perineural invasion, tumor budding, fewer tumor-infiltrating lymphocytes, higher pT and pN category, and frequent distant metastasis. In contrast, tumors overexpressing SMAD4 showed a significant association with sporadic microsatellite instability. After adjustment for TNM stage, tumor differentiation, adjuvant chemotherapy, and lymphovascular invasion, the loss of SMAD4 was found to be an independent prognostic factor for worse 5-year progression-free survival (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.01 to 1.60; p=.042) and 7-year cancer-specific survival (HR, 1.45; 95% CI, 1.06 to 1.99; p=.022). Conclusions We confirmed the value of determining the loss of SMAD4 immunohistochemically as an independent prognostic factor for CRC in general. In addition, we identified some histologic and molecular features that might be clues to elucidate the role of SMAD4 in colorectal tumorigenesis and progression.
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Affiliation(s)
- Seung-Yeon Yoo
- Department of Pathology, Seoul National University Hospital, Seoul, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Ji-Ae Lee
- Department of Pathology, Seoul National University Hospital, Seoul, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Yunjoo Shin
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Nam-Yun Cho
- Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Jeong Mo Bae
- Department of Pathology, Seoul National University Hospital, Seoul, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
| | - Gyeong Hoon Kang
- Department of Pathology, Seoul National University Hospital, Seoul, Korea.,Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea
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16
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Siraj AK, Pratheeshkumar P, Divya SP, Parvathareddy SK, Bu R, Masoodi T, Kong Y, Thangavel S, Al-Sanea N, Ashari LH, Abduljabbar A, Al-Homoud S, Al-Dayel F, Al-Kuraya KS. TGFβ-induced SMAD4-dependent Apoptosis Proceeded by EMT in CRC. Mol Cancer Ther 2019; 18:1312-1322. [PMID: 31053577 DOI: 10.1158/1535-7163.mct-18-1378] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2018] [Revised: 04/28/2019] [Accepted: 04/29/2019] [Indexed: 11/16/2022]
Abstract
Colorectal cancer is one of the leading causes of cancer-related deaths worldwide. In Saudi Arabia, colorectal cancer is more aggressive and presents at younger age, warranting new treatment strategies. Role of TGFβ/Smad4 signaling pathway in initiation and progression of colorectal cancer is well documented. This study examined the role of TGFβ/Smad4 signaling pathway in a large cohort of Saudi patients with colorectal cancer, followed by in vitro analysis to dissect the dual role of TGFβ on inducing epithelial-to-mesenchymal transition (EMT) and apoptosis. Our study demonstrated high frequency of Smad4 alterations with low expression of Smad4 protein identifying a subgroup of aggressive colorectal cancer to be an independent marker for poor prognosis. Functional studies using colorectal cancer cells show that TGFβ induces Smad4-dependent EMT followed by apoptosis. Induction of mesenchymal transcriptional factors, Snail1 and Zeb1, was essential for TGFβ-induced apoptosis. Our results indicate that KLF5 acts as an oncogene in colorectal cancer cells regardless of Smad4 expression and inhibition of KLF5 is requisite for TGFβ-induced apoptosis. Furthermore, TGFβ/Smad4 signal inhibits the transcription of KLF5 that in turn switches Sox4 from tumor promoter to suppressor. A high incidence of Smad4 alterations were found in the Saudi patients with colorectal cancer. Functional study results indicate that TGFβ induces Smad4-dependent EMT followed by apoptosis in colorectal cancer cells.
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Affiliation(s)
- Abdul K Siraj
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Poyil Pratheeshkumar
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Sasidharan Padmaja Divya
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | | | - Rong Bu
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Tariq Masoodi
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Yan Kong
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Saravanan Thangavel
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Nasser Al-Sanea
- Department of Surgery, Colorectal Unit, Riyadh, Saudi Arabia
| | - Luai H Ashari
- Department of Surgery, Colorectal Unit, Riyadh, Saudi Arabia
| | | | - Samar Al-Homoud
- Department of Surgery, Colorectal Unit, Riyadh, Saudi Arabia
| | - Fouad Al-Dayel
- Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Khawla S Al-Kuraya
- Human Cancer Genomic Research, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
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17
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Liu L, Liu H, Zhou Y, He J, Liu Q, Wang J, Zeng M, Yuan D, Tan F, Zhou Y, Pei H, Zhu H. HLTF suppresses the migration and invasion of colorectal cancer cells via TGF‑β/SMAD signaling in vitro. Int J Oncol 2018; 53:2780-2788. [PMID: 30320371 DOI: 10.3892/ijo.2018.4591] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 09/25/2019] [Indexed: 11/06/2022] Open
Abstract
Helicase‑like transcription factor (HLTF) has been identified as a tumor suppressor gene. The hypermethylation of HTLF is frequently observed in various types of cancer, including colorectal cancer (CRC). However, the mechanisms through which HLTF suppresses CRC progression remain unclear. Thus, the aim of the present study was to explore the biological function of HLTF in CRC cells and the underlying mechanisms. CRC tissues and cells were used to detect the expression of HLTF. Wound‑healing and Transwell assays were performed to assess the motility of CRC cells. The results revealed that HLTF expression was significantly associated with the differentiation status, invasion depth, lymph node metastasis and distant metastasis. A low HLTF expression was significantly associated with a poor survival. Furthermore, HTLF knockdown or ectopic overexpression significantly promoted or suppressed the motility of CRC cells, respectively. With regard to the underlying molecular mechanisms, the protein expression of HTLF was upregulated when the CRC cells were stimulated with transforming growth factor (TGF)‑β, and HLTF upregulation induced an increase in SMAD4 and p‑SMAD2/3 expression and a decrease in levels of the TGF‑β/SMAD pathway downstream genes, Vimentin and zinc finger e‑box binding homeobox 1 (ZEB1). On the whole, the findings of this study suggest that HLTF is negatively associated with the progression of CRC, and its overexpression suppresses the migration and invasion of CRC cells by targeting the TGF‑β/SMAD pathway.
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Affiliation(s)
- Li Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Huan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yangying Zhou
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Jiaofeng He
- Department of Oncology, Hunan Academy of Traditional Chinese Medicine Affiliated Hospital, Changsha, Hunan 410008, P.R. China
| | - Qiong Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Jian Wang
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Manting Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Dan Yuan
- Department of Oncology, Zhuzhou No. 2 Hospital, Zhuzhou, Hunan 412005, P.R. China
| | - Fengbo Tan
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Yuan Zhou
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Haiping Pei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
| | - Hong Zhu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, P.R. China
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18
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Zhao M, Mishra L, Deng CX. The role of TGF-β/SMAD4 signaling in cancer. Int J Biol Sci 2018; 14:111-123. [PMID: 29483830 PMCID: PMC5821033 DOI: 10.7150/ijbs.23230] [Citation(s) in RCA: 399] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Accepted: 11/19/2017] [Indexed: 12/13/2022] Open
Abstract
Transforming growth factor β (TGF-β) signaling pathway plays important roles in many biological processes, including cell growth, differentiation, apoptosis, migration, as well as cancer initiation and progression. SMAD4, which serves as the central mediator of TGF-β signaling, is specifically inactivated in over half of pancreatic duct adenocarcinoma, and varying degrees in many other types of cancers. In the past two decades, multiple studies have revealed that SMAD4 loss on its own does not initiate tumor formation, but can promote tumor progression initiated by other genes, such as KRAS activation in pancreatic duct adenocarcinoma and APC inactivation in colorectal cancer. In other cases, such as skin cancer, loss of SMAD4 plays an important initiating role by disrupting DNA damage response and repair mechanisms and enhance genomic instability, suggesting its distinct roles in different types of tumors. This review lists SMAD4 mutations in various types of cancer and summarizes recent advances on SMAD4 with focuses on the function, signaling pathway, and the possibility of SMAD4 as a prognostic indicator.
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Affiliation(s)
- Ming Zhao
- Faculty of Health Sciences, University of Macau, Macau SAR, China.,Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Lopa Mishra
- Center for Translational Research, Department of Surgery and GW Cancer Center, George Washington University, Washington DC, USA
| | - Chu-Xia Deng
- Faculty of Health Sciences, University of Macau, Macau SAR, China
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19
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Jia X, Shanmugam C, Paluri RK, Jhala NC, Behring MP, Katkoori VR, Sugandha SP, Bae S, Samuel T, Manne U. Prognostic value of loss of heterozygosity and sub-cellular localization of SMAD4 varies with tumor stage in colorectal cancer. Oncotarget 2017; 8:20198-20212. [PMID: 28423626 PMCID: PMC5386755 DOI: 10.18632/oncotarget.15560] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Accepted: 01/24/2017] [Indexed: 12/24/2022] Open
Abstract
Background Although loss of heterozygosity (LOH) at chromosome location 18q21 and decreased expression of SMAD4 in invasive colorectal cancers (CRCs) correlate with poor patient survival, the prognostic value of LOH at 18q21 and sub-cellular localization of SMAD4 have not been evaluated in relation to tumor stage. Methods Genomic DNA samples from 209 formalin-fixed, paraffin-embedded sporadic CRC tissues and their matching controls were analyzed for 18q21 LOH, and corresponding tissue sections were evaluated by immunohistochemistry for expression of SMAD4 and assessed for its sub-cellular localization (nuclear vs. cytoplasmic). In addition, 53 frozen CRCs and their matching control tissues were analyzed for their mutational status and mRNA expression of SMAD4. The phenotypic expression pattern and LOH status were evaluated for correlation with patient survival by the use of Kaplan-Meier and Cox regression models. Results LOH of 18q21 was detected in 61% of the informative cases. In 8% of the cases, missense point mutations were detected in Smad4. In CRCs, relative to controls, there was increased SMAD4 staining in the cytoplasm (74%) and decreased staining in the nuclei (37%). LOH of 18q21 and high cytoplasmic localization of SMAD4 were associated with shortened overall survival of Stage II patients, whereas low nuclear expression of SMAD4 was associated with worse survival, but only for patients with Stage III CRCs. Conclusions LOH of 18q21 and high cytoplasmic localization of SMAD4 in Stage II CRCs and low nuclear SMAD4 in Stage III CRCs are predictors of shortened patient survival.
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Affiliation(s)
- Xu Jia
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Chandrakumar Shanmugam
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Current address: Department of Pathology, ESIC Medical College and Hospital, Sanathnagar, Hyderabad, Telangana, India
| | - Ravi K Paluri
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Nirag C Jhala
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Current address: Pathology & Laboratory Medicine, Temple University, Philadelphia, PA, USA
| | - Michael P Behring
- Department of Epidemiology, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Venkat R Katkoori
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Current address: Department of Surgery, Michigan State University, College of Human Medicine, Lansing, MI, USA
| | - Shajan P Sugandha
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Sejong Bae
- Department of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Temesgen Samuel
- College of Veterinary Medicine, Tuskegee University, Tuskegee, AL, USA
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.,Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA
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20
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Berretta M, Alessandrini L, De Divitiis C, Nasti G, Lleshi A, Di Francia R, Facchini G, Cavaliere C, Buonerba C, Canzonieri V. Serum and tissue markers in colorectal cancer: State of art. Crit Rev Oncol Hematol 2017; 111:103-116. [PMID: 28259285 DOI: 10.1016/j.critrevonc.2017.01.007] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Revised: 12/15/2016] [Accepted: 01/10/2017] [Indexed: 12/14/2022] Open
Abstract
Colorectal cancer (CRC) represents one of the most commonly diagnosed cancers worldwide. It is the second leading cause of cancer death in Western Countries. In the last decade, the survival of patients with metastatic CRC has improved dramatically. Due to the advent of new drugs (irinotecan and oxaliplatin) and target therapies (i.e. bevacizumab, cetuximab, panitumab, aflibercept and regorafenib), the median overall survival has risen from about 12 mo in the mid nineties to 30 mo recently. Molecular studies have recently widened the opportunity for testing new possible markers, but actually, only few markers can be recommended for practical use in clinic. In the next future, the hope is to have a complete panel of clinical biomarkers to use in every setting of CRC disease, and at the same time: 1) to receive information about prognostic significance by their expression and 2) to be oriented in the choice of the adequate treatment. Moreover, molecular analyses have shown that the natural history of all CRCs is not the same. Individual patients with same stage tumors may have different long-term prognosis and response to therapy. In addition, some prognostic variables are likely to be more important than others. Here we review the role of serum and tissue markers according to the recently published English literature. This paper is an extension of the article "Biological and clinical markers in colorectal cancer: state of art" by Cappellani A published in Jan 2010.
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Affiliation(s)
- Massimiliano Berretta
- Department of Medical Oncology, National Cancer Institute, Centro di Riferimento Oncologico of Aviano, IRCCS, 33081 Aviano, PN, Italy.
| | - Lara Alessandrini
- Division of Pathology, National Cancer Institute, Centro di Riferimento Oncologico of Aviano, IRCCS, 33081 Aviano, PN, Italy
| | - Chiara De Divitiis
- Department of Medical Oncology, National Cancer Institute IRCCS Pascale, Naples, Italy
| | - Guglielmo Nasti
- Department of Medical Oncology, National Cancer Institute IRCCS Pascale, Naples, Italy
| | - Arben Lleshi
- Department of Medical Oncology, National Cancer Institute, Centro di Riferimento Oncologico of Aviano, IRCCS, 33081 Aviano, PN, Italy
| | - Raffaele Di Francia
- Hematology-Oncology and Stem Cell Transplantation Unit, National Cancer Institute IRCCS Pascale, Naples, Italy
| | - Gaetano Facchini
- Division of Medical Oncology, Department of Uro-Gynaecological Oncology, Istituto Nazionale Tumori "Fondazione G. Pascale" - IRCCS, Naples, Italy
| | - Carla Cavaliere
- Department of Onco-Ematology Medical Oncology, S.G. Moscati Hospital of Taranto, Taranto, Italy
| | - Carlo Buonerba
- Department of Clinical Medicine and Surgery, University Federico II of Naples, Naples, Italy
| | - Vincenzo Canzonieri
- Division of Pathology, National Cancer Institute, Centro di Riferimento Oncologico of Aviano, IRCCS, 33081 Aviano, PN, Italy
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21
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Seldon CS, Colbert LE, Hall WA, Fisher SB, Yu DS, Landry JC. Chromodomain-helicase-DNA binding protein 5, 7 and pronecrotic mixed lineage kinase domain-like protein serve as potential prognostic biomarkers in patients with resected pancreatic adenocarcinomas. World J Gastrointest Oncol 2016; 8:358-365. [PMID: 27096031 PMCID: PMC4824714 DOI: 10.4251/wjgo.v8.i4.358] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2015] [Revised: 12/05/2015] [Accepted: 01/11/2016] [Indexed: 02/05/2023] Open
Abstract
Pancreatic cancer is one of the deadliest cancers with a very poor prognosis. Recently, there has been a significant increase in research directed towards identifying potential biomarkers that can be used to diagnose and provide prognostic information for pancreatic cancer. These markers can be used clinically to optimize and personalize therapy for individual patients. In this review, we focused on 3 biomarkers involved in the DNA damage response pathway and the necroptosis pathway: Chromodomain-helicase-DNA binding protein 5, chromodomain-helicase-DNA binding protein 7, and mixed lineage kinase domain-like protein. The aim of this article is to review present literature provided for these biomarkers and current studies in which their effectiveness as prognostic biomarkers are analyzed in order to determine their future use as biomarkers in clinical medicine. Based on the data presented, these biomarkers warrant further investigation, and should be validated in future studies.
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22
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Voorneveld PW, Jacobs RJ, Kodach LL, Hardwick JCH. A Meta-Analysis of SMAD4 Immunohistochemistry as a Prognostic Marker in Colorectal Cancer. Transl Oncol 2015; 8:18-24. [PMID: 25749173 PMCID: PMC4350636 DOI: 10.1016/j.tranon.2014.11.003] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2014] [Revised: 11/02/2014] [Accepted: 11/05/2014] [Indexed: 01/17/2023] Open
Abstract
AIM: SMAD4 immunohistochemistry is considered a valuable prognostic marker in colorectal cancer, but individual studies have often been small and the results variable. A meta-analysis could potentially clarify these findings. METHODS: In September 2014, a Pubmed and Google Scholar search was conducted to find publications that reported the prognostic value of SMAD4 expression. A meta-analysis was performed to clarify the association between SMAD4 expression and survival outcomes. RESULTS: 137 studies were found, of which 13 were considered eligible. The studies consisted of a total of 3800 patients. Three different endpoints were taken into account, namely, overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS). In addition, the studies were divided into univariate and multivariate analyses. The pooled hazard ratios were given as follows: univariate CSS = 1.75 [95% confidence interval (CI): 0.93-3.32; z= 1.69; P= .09]; multivariate CSS = 2.17 (95% CI: 1.56-3.01; z= 4.65; P= .000); univariate DFS = 2.11 (95% CI: 1.36-3.28; z= 3.32; P= .001); multivariate DFS = 2.15 (95% CI: 1.56-3.01; z= 4.65; P= .000); univariate OS and DFS = 2.30 (95% CI: 1.41-3.73; z= 3.36; P= .001); univariate OS = 2.28 (95% CI: 1.30-4.00; z= 2.89; P= .004). CONCLUSION: The results of the presented meta-analyses indicate that SMAD4 expression status using immunohistochemistry is a prognostic marker for patient survival.
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Affiliation(s)
- Philip W Voorneveld
- Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands.
| | - Rutger J Jacobs
- Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands
| | - Liudmila L Kodach
- Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands
| | - James C H Hardwick
- Department of Gastroenterology, Leiden University Medical Center, Leiden, The Netherlands
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23
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Du Y, Zhou X, Huang Z, Qiu T, Wang J, Zhu W, Wang T, Liu P. Meta-analysis of the prognostic value of smad4 immunohistochemistry in various cancers. PLoS One 2014; 9:e110182. [PMID: 25333693 PMCID: PMC4198206 DOI: 10.1371/journal.pone.0110182] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2014] [Accepted: 09/07/2014] [Indexed: 12/17/2022] Open
Abstract
Background Accumulating evidence indicates that Smad4 (DPC4) plays a fundamental role in the development and prognosis of several types of cancer. The objective of this study was to conduct a meta-analysis to evaluate whether the loss of Smad4 staining could serve as a prognostic marker. Methods A comprehensive meta-analysis was conducted using major useful databases to determine the relationship between the immunohistochemical detection of Smad4 and the survival of patients with various cancers. We used hazard ratios (HRs) with 95% confidence interval (CIs) as the effect estimation to evaluate the association of Smad4 with overall survival (OS), cancer-specific survival (CSS) or recurrence-free survival (RFS). The relationship between the clinical characteristics of patients and Smad4 was also evaluated using the odds ratio (OR). Results A total of 7570 patients from 26 studies were included in the analysis. The pooled results showed that loss of Smad4 staining was a negative predictor of OS with an HR of 1.97 (95% CI: 1.55–2.51; Pheterogeneity<0.001) and CSS/RFS (HR = 1.81; 95% CI: 1.30–2.54; Pheterogeneity<0.001). In addition, loss of Smad4 staining was more likely to be found in older (OR = 1.69, 95% CI: 1.09–2.61; Pheterogeneity = 0.648) colorectal cancer patients with a late tumor stage (OR = 2.31, 95% CI: 1.71–3.10; Pheterogeneity = 0.218) and in gastric cancer patients with lymph node metastasis (OR = 2.11, 95% CI: 1.03–4.34; Pheterogeneity = 0.038). Conclusion Based on these results, our meta-analysis provided evidence that loss of Smad4 staining could act as an unfavorable biomarker in the prognosis of various cancers and should be used as a powerful tool in future clinical trials.
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Affiliation(s)
- Yiping Du
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Xin Zhou
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Zebo Huang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tianzhu Qiu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jian Wang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Wei Zhu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Tongshan Wang
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- * E-mail: (TSW); (PL)
| | - Ping Liu
- Department of Oncology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China
- Cancer Center of Nanjing Medical University, Nanjing, China
- * E-mail: (TSW); (PL)
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24
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McAlister GC, Nusinow DP, Jedrychowski MP, Wühr M, Huttlin EL, Erickson BK, Rad R, Haas W, Gygi SP. MultiNotch MS3 enables accurate, sensitive, and multiplexed detection of differential expression across cancer cell line proteomes. Anal Chem 2014; 86:7150-8. [PMID: 24927332 PMCID: PMC4215866 DOI: 10.1021/ac502040v] [Citation(s) in RCA: 959] [Impact Index Per Article: 87.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
![]()
Multiplexed quantitation via isobaric
chemical tags (e.g., tandem
mass tags (TMT) and isobaric tags for relative and absolute quantitation
(iTRAQ)) has the potential to revolutionize quantitative proteomics.
However, until recently the utility of these tags was questionable
due to reporter ion ratio distortion resulting from fragmentation
of coisolated interfering species. These interfering signals can be
negated through additional gas-phase manipulations (e.g., MS/MS/MS
(MS3) and proton-transfer reactions (PTR)). These methods, however,
have a significant sensitivity penalty. Using isolation waveforms
with multiple frequency notches (i.e., synchronous precursor selection,
SPS), we coisolated and cofragmented multiple MS2 fragment ions, thereby
increasing the number of reporter ions in the MS3 spectrum 10-fold
over the standard MS3 method (i.e., MultiNotch MS3). By increasing
the reporter ion signals, this method improves the dynamic range of
reporter ion quantitation, reduces reporter ion signal variance, and
ultimately produces more high-quality quantitative measurements. To
demonstrate utility, we analyzed biological triplicates of eight colon
cancer cell lines using the MultiNotch MS3 method. Across all the
replicates we quantified 8 378 proteins in union and 6 168
proteins in common. Taking into account that each of these quantified
proteins contains eight distinct cell-line measurements, this data
set encompasses 174 704 quantitative ratios each measured in
triplicate across the biological replicates. Herein, we demonstrate
that the MultiNotch MS3 method uniquely combines multiplexing capacity
with quantitative sensitivity and accuracy, drastically increasing
the informational value obtainable from proteomic experiments.
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Affiliation(s)
- Graeme C McAlister
- Harvard Medical School, Department of Cell Biology , Boston, Massachusetts 02115, United States
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25
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Kim JH, Kang GH. Molecular and prognostic heterogeneity of microsatellite-unstable colorectal cancer. World J Gastroenterol 2014; 20:4230-4243. [PMID: 24764661 PMCID: PMC3989959 DOI: 10.3748/wjg.v20.i15.4230] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2013] [Revised: 01/30/2014] [Accepted: 02/20/2014] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancers (CRCs) with a high level of microsatellite instability (MSI-H) are clinicopathologically distinct tumors characterized by predominance in females, proximal colonic localization, poor differentiation, mucinous histology, tumor-infiltrating lymphocytes, a Crohn’s-like lymphoid reaction and a favorable prognosis. In terms of their molecular features, MSI-H CRCs are heterogeneous tumors associated with various genetic and epigenetic alterations, including DNA mismatch repair deficiency, target microsatellite mutations, BRAF mutations, a CpG island methylator phenotype-high (CIMP-H) status, and a low level of genomic hypomethylation. The molecular heterogeneity of MSI-H CRCs also depends on ethnic differences; for example, in Eastern Asian countries, relatively low frequencies of CIMP-H and BRAF mutations have been observed in MSI-H CRCs compared to Western countries. Although the prognostic features of MSI-H CRCs include a favorable survival of patients and low benefit of adjuvant chemotherapy, there may be prognostic differences based on the molecular heterogeneity of MSI-H CRCs. Here, we have reviewed and discussed the molecular and prognostic features of MSI-H CRCs, as well as several putative prognostic or predictive molecular markers, including HSP110 expression, beta2-microglobulin mutations, myosin 1a expression, CDX2/CK20 expression, SMAD4 expression, CIMP status and LINE-1 methylation levels.
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26
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Expression status of wild-type HSP110 correlates with HSP110 T17 deletion size and patient prognosis in microsatellite-unstable colorectal cancer. Mod Pathol 2014; 27:443-53. [PMID: 24030751 DOI: 10.1038/modpathol.2013.160] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2013] [Revised: 07/22/2013] [Accepted: 07/24/2013] [Indexed: 12/26/2022]
Abstract
It has been recently suggested that the expression levels of mutant HSP110 could be a prognostic marker in colorectal cancer with a high level of microsatellite instability (MSI-H). The aim of our study was to validate the prognostic significance of HSP110 mutation using immunohistochemistry and DNA testing in MSI-H colorectal cancer. Wild-type HSP110 (HSP110wt)-specific immunohistochemistry was performed in 168 MSI-H colorectal cancer tissues, and their expression levels were evaluated using a four-tier scoring system (0/1+/2+/3+). Of these tissues, 167 cases were analyzed for HSP110 T17 deletion. Associations with clinicopathological, molecular and survival parameters were statistically analyzed. The low-level expression of HSP110wt (0/1+) was observed in 40 MSI-H colorectal cancers (24%) and was significantly related to large HSP110 T17 deletions (≥ 4 bp, P<0.001). In survival analysis, patients with low HSP110wt expression (0/1+) showed better disease-free survival compared with those with high expression (2+/3+; P=0.005). This significance in survival difference was maintained in patients with 5-fluorouracil-based chemotherapy-treated tumors (P=0.024) and in those with stage III/IV tumors (P=0.032). Multivariate analysis confirmed the role of HSP110wt expression as an independent prognostic factor (P=0.016, hazard ratio=4.32). In MSI-H colorectal cancer, a low expression of HSP110wt is associated with large HSP110 T17 deletions and better clinical outcome. Immunohistochemistry of HSP110wt can be a simple and valuable tool for the prognostic and therapeutic stratification of patients with MSI-H colorectal cancer.
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27
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Bellizzi AM. Contributions of molecular analysis to the diagnosis and treatment of gastrointestinal neoplasms. Semin Diagn Pathol 2013; 30:329-61. [DOI: 10.1053/j.semdp.2013.11.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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28
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Ai X, Wu Y, Zhang W, Zhang Z, Jin G, Zhao J, Yu J, Lin Y, Zhang W, Liang H, Datta PK, Zhang M, Zhang B, Chen X. Targeting the ERK pathway reduces liver metastasis of Smad4-inactivated colorectal cancer. Cancer Biol Ther 2013; 14:1059-67. [PMID: 24025354 DOI: 10.4161/cbt.26427] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Transforming growth factor β (TGF-β)/Smad signaling is involved in colorectal carcinoma (CRC) development and progression. The frequent loss of SMAD4 is associated with liver metastasis and poor prognosis of CRC, but the underlying mechanism remains elusive. This study aimed to elucidate the role of Smad-independent TGF-β signaling in CRC metastasis. Immunohistochemistry showed that Smad4 level was negatively correlated with TNM stage and phospho-ERK level in human CRCs and liver metastasis samples. Knockdown of Smad4 in CT26 and HCT116 cells activated ERK pathway, altered the expression of MMP2 and COX-2, promoted cell motility, migration, and invasion in vitro, enhanced metastasis, and shortened the survival of metastatic tumor-bearing mice. MEK inhibitor U0126 and GSK1120212 inhibited the motility, migration, and invasion of Smad4 knockdown cells, inhibited metastasis, and prolonged the survival of metastatic tumor-bearing mice. Furthermore, MEK inhibitor could reverse the changes of phospho-ERK, MMP2, and COX-2 levels. In conclusion, our results indicate that ERK pathway plays a key oncogenic role in CRC with SMAD4 inactivation mutations, and implicate ERK as a potential therapeutic target for CRC liver metastasis.
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Affiliation(s)
- Xi Ai
- Hepatic Surgery Center; Tongji Hospital; Tongji Medical College; Huazhong University of Science and Technology; Wuhan, PR China
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Epigenetics meets radiation biology as a new approach in cancer treatment. Int J Mol Sci 2013; 14:15059-73. [PMID: 23873297 PMCID: PMC3742287 DOI: 10.3390/ijms140715059] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2013] [Revised: 07/10/2013] [Accepted: 07/15/2013] [Indexed: 02/06/2023] Open
Abstract
Cancer is a disease that results from both genetic and epigenetic changes. In recent decades, a number of people have investigated the disparities in gene expression resulting from variable DNA methylation alteration and chromatin structure modification in response to the environment. Especially, colon cancer is a great model system for investigating the epigenetic mechanism for aberrant gene expression alteration. Ionizing radiation (IR) could affect a variety of processes within exposed cells and, in particular, cause changes in gene expression, disruption of cell cycle arrest, and apoptotic cell death. Even though there is growing evidence on the importance of epigenetics and biological processes induced by radiation exposure in various cancer types including colon cancer, specific epigenetic alterations induced by radiation at the molecular level are incompletely defined. This review focuses on discussing possible IR-mediated changes of DNA methylation and histone modification in cancer.
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30
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Xia RH, Song XM, Wang XJ, Li J, Mao L. The combination of SMAD4 expression and histological grade of dysplasia is a better predictor for the malignant transformation of oral leukoplakia. PLoS One 2013; 8:e66794. [PMID: 23826135 PMCID: PMC3691281 DOI: 10.1371/journal.pone.0066794] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2013] [Accepted: 05/13/2013] [Indexed: 12/13/2022] Open
Abstract
Oral leukoplakia (OL) is the most common premalignancy in the oral cavity and can progress to oral squamous cell carcinoma (OSCC). SMAD4 is a tumor suppressor implicated in multiple cancer types including OSCC. To assess the role of SMAD4 in oral leukoplakia malignant transformation, the authors investigated SMAD4 expression patterns in OL and OSCC using a highly specific antibody and correlated the patterns with the risk of malignant transformation oral leukoplakia. Immunohistochemistry and a quantitative imaging system were used to measure SMAD4 expression in OL from 88 OL patients, including 22 who later went through malignant transformation, and their OSCC counterpart. Forty-three (48.9%) of the 88 OL patients had strong SMAD4 expression. SMAD4 expression had no significant correlation with patients' clinicopathological parameters. Interestingly, 17 (39.5%) of the 43 OL lesions with strong SMAD4 expression went through malignant transformation whereas only 5 (11.1%) of the 45 OL lesions with weak SMAD4 expression did so (p = 0.002). The SMAD4 expression in OL was much higher than that in their OSCC counterpart. Kaplan-Meier analysis revealed that the combination of SMAD4 expression and histological grade of dysplasia (p = 0.007) is a better predictor for the malignant transformation of oral leukoplakia. In the multivariate analysis, both SMAD4 expression and grade of dysplasia were identified as independent factors for OL malignant transformation risk (p = 0.013 and 0.021, respectively). It was concluded that high SMAD4 expression may be indicative of an early carcinogenic process in OL and serve as an independent biomarker in assessing malignant transformation risk in patients with OL, and the combination of SMAD4 expression and histological grade of dysplasia is a better predictor for the malignant transformation of oral leukoplakia.
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Affiliation(s)
- Rong-Hui Xia
- Department of Oral Pathology, 9th People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China
- Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland, United States of America
| | - Xiao-Meng Song
- Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland, United States of America
- Department of Oral Maxillofacial–Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Xiao-Jing Wang
- Department of Oral Maxillofacial–Head and Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China
| | - Jiang Li
- Department of Oral Pathology, 9th People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai Key Laboratory of Stomatology, Shanghai, China
- * E-mail: (JL); (LM)
| | - Li Mao
- Department of Oncology and Diagnostic Sciences, Dental School, University of Maryland, Baltimore, Maryland, United States of America
- * E-mail: (JL); (LM)
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31
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Santos C, Vilar E, Capella G, Salazar R. Molecular markers in colorectal cancer: clinical relevance in stage II colon cancer. COLORECTAL CANCER 2013. [DOI: 10.2217/crc.13.24] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
SUMMARY Colorectal cancer is the second most common cause of cancer death in developed countries. Adjuvant chemotherapy is standard for stage III colorectal cancer but its use in stage II is controversial. Several clinicopathological factors have been described to define a high-risk group among stage II colon cancers, which can aid the selection of patients who may benefit from chemotherapy. Local tumor invasion (T4), high histological grade, obstruction and perforation at diagnosis, and number of lymph nodes removed are the most widely accepted factors. Several molecular factors have been also investigated as prognostic candidate biomarkers. DNA ploidy, KRAS and TP53 mutations, thymidylate synthase, dihydropyrimidine dehydrogenase, thymidine phosphorylase, loss of heterozygosity on chromosome 18q and microsatellite instability have been widely investigated. The aim of this review is to analyze the current evidence and clinical applications of the classical molecular biomarkers as well as new ones such as BRAF, circulating tumor cells, genome expression signatures and DNA methylation.
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Affiliation(s)
- Cristina Santos
- Department of Medical Oncology, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
- Translational Research Laboratory, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Gabriel Capella
- Translational Research Laboratory, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
| | - Ramon Salazar
- Translational Research Laboratory, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
- Department of Medical Oncology, Institut Català d’Oncologia – Institut d’Investigació Biomèdica de Bellvitge (IDIBELL), L’Hospitalet de Llobregat, Barcelona, 08907, Spain
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32
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Malkoski SP, Wang XJ. Two sides of the story? Smad4 loss in pancreatic cancer versus head-and-neck cancer. FEBS Lett 2012; 586:1984-92. [PMID: 22321641 DOI: 10.1016/j.febslet.2012.01.054] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2012] [Revised: 01/26/2012] [Accepted: 01/27/2012] [Indexed: 12/31/2022]
Abstract
TGFβ signaling Smads (Smad2, 3, and 4) were suspected tumor suppressors soon after their discovery. Nearly two decades of research confirmed this role and revealed other divergent and cancer-specific functions including paradoxical tumor promotion effects. Although Smad4 is the most potent tumor suppressor, its functions are highly context-specific as exemplified by pancreatic cancer and head-and-neck cancer: in pancreatic cancer, Smad4 loss cannot initiate tumor formation but promotes metastases while in head-and-neck cancer Smad4 loss promotes cancer progression but also initiates tumor formation, likely through effects on genomic instability. The differing consequences of impaired Smad signaling in human cancers and the molecular mechanisms that underpin these differences will have important implications for the design and application of novel targeted therapies.
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Affiliation(s)
- Stephen P Malkoski
- Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, United States
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33
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Abstract
Colorectal cancer (CRC) develops through a multistep process that results from the progressive accumulation of mutations and epigenetic alterations in tumor suppressor genes and oncogenes. Epigenetic modifications, that have a fundamental role in the regulation of gene expression, involve DNA methylation, specific histone modifications and non-coding RNAs (ncRNAs) interventions. Many genes have been until now studied to detect their methylation status during CRC carcinogenesis; and the functions of many of these genes in cancer initiation and progression are being clarified. Less is known about the patterns of histone modification alterations in CRC. Epigenetic deregulation of the ncRNAs or the genes involved in their biogenesis have been described in tumor progression and some examples of dysregulated microRNA were found also in CRC cells. Diet has an important role in the etiology of colon cancer. Folate is involved via 5-methyltetrahydrofolate in the conversion of homocysteine to methionine, which is then used to form the main DNA methylating agent S-adenosylmethionine. However, the role of folate in protecting from or in promoting CRC, depending on conditions, is still debated. The study of epigenetic marks to better characterize CRC and to identify new tools for diagnosis and prognosis as well as for therapeutic interventions is extremely promising.
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Affiliation(s)
- F Migheli
- Department of Surgery Department of Human and Environmental Sciences, University of Pisa, Via S. Giuseppe 22, Pisa, Italy
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