Molecular Pathways: Microsatellite Instability in Colorectal Cancer: Prognostic, Predictive, and Therapeutic Implications
- 14 March 2012
- journal article
- Published by American Association for Cancer Research (AACR) in Clinical Cancer Research
- Vol. 18 (6), 1506-1512
- https://doi.org/10.1158/1078-0432.ccr-11-1469
Abstract
Microsatellite instability (MSI) is the molecular fingerprint of the deficient mismatch repair (MMR) system, which characterizes ∼15% of colorectal cancers. MSI develops as a result of germline mutations in MMR genes or, more commonly, from epigenetic silencing of MLH1 in sporadic tumors occurring in a background of methylation of CpG islands in gene promoter regions and in tumors that frequently show hotspot mutations in the BRAF oncogene. MSI tumors have distinct phenotypic features and have been consistently associated with a better stage-adjusted prognosis compared with microsatellite stable tumors. MSI negatively predicts response to 5-fluorouracil and may also determine responsiveness to other drugs used for treatment of colorectal cancers. Recent data have expanded the molecular heterogeneity of MSI tumors and may contribute to our understanding of differential chemosensitivity. The ability to identify deficient MMR has important implications for patient management, and it holds promise for therapeutic exploitation and for the development of novel therapeutics. Clin Cancer Res; 18(6); 1506–12. ©2012 AACR.This publication has 62 references indexed in Scilit:
- 5-Fluorouracil Adjuvant Chemotherapy Does Not Increase Survival in Patients With CpG Island Methylator Phenotype Colorectal CancerGastroenterology, 2011
- Methotrexate induces oxidative DNA damage and is selectively lethal to tumour cells with defects in the DNA mismatch repair gene MSH2EMBO Molecular Medicine, 2009
- Deficient mismatch repair system in patients with sporadic advanced colorectal cancerBritish Journal of Cancer, 2009
- Genomic and Epigenetic Instability in Colorectal Cancer PathogenesisGastroenterology, 2008
- Microsatellite instability due to hMLH1 deficiency is associated with increased cytotoxicity to irinotecan in human colorectal cancer cell linesBritish Journal of Cancer, 2008
- CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancerNature Genetics, 2006
- Recognition and processing of cisplatin- and oxaliplatin-DNA adductsCritical Reviews in Oncology/Hematology, 2005
- RAF/RAS oncogenes and mismatch-repair statusNature, 2002
- Mutations of the BRAF gene in human cancerNature, 2002
- Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancerThe Lancet, 2000