Novel genetic and epigenetic alterations in ... - Ous-research.no

Critical Reviews TM in Oncogenesis, 13(3):229–257 (2007)Slip Slidin’ Away: A DuodecennialReview of Targeted Genesin Mismatch Repair DeficientColorectal CancerEllen C. Røyrvik, 1,2 1,2 3,4Terje Ahlquist, Torbjørn Rognes, &Ragnhild A. Lothe 1,2,51 Department of Cancer Prevention, Institute for Cancer Research, Rikshospitalet-RadiumhospitaletMedical Center, Norway2 Center for Cancer Biomedicine, University of Oslo, Norway3 Center for Molecular Biology and Neuroscience, Rikshospitalet-Radiumhospitalet Medical Center4 Department of Informatics, University of Oslo, Norway5 Department of Molecular Biosciences, University of Oslo, NorwayAddress all correspondence to Ragnhild A. Lothe, Department of Cancer Prevention, Institute forCancer Research, Rikshospitalet-Radiumhospitalet Medical Center, Norway; rlothe@rr-research.noABSTRACT: Roughly 15% of colorectal tumors are characterized by microsatellite instability(MSI), a deficiency caused by defective DNA mismatch repair, which leads toprofuse insertions and deletions in microsatellites. Downstream target genes of this defectiverepair are those prone to exhibit these insertion/deletion mutations in their codingregions and potentially having functional consequences in, and providing a growth advantagefor, the cancer cell. This review presents the last 12 years of research on theseMSI target genes, systematizing the mutation details of the more than 160 genes identifiedto date, and includes their mutation frequencies in colorectal and other MSI (e.g.,gastric and endometrial) tumors. Functional aspects of certain targets and the target geneconcept itself are also discussed, as is the comparative wealth of potential target genes—assessed by scanning the coding sequences of the human genome for mononucleotide repeats—yetto be investigated.KEYWORDS: Colon carcinoma, microsatellite instability, coding microsatellites, DNAmismatch repair, target genesI. INTRODUCTION1Colorectal cancer is one of the most common cancer types to affect both sexes.It is thought to derive from stem cells in colonic crypts, where there is a naturallyhigh cellular turnover, a characteristic that may well favor the acquisition of neo-0893–9675/07/$35.00 229© 2007 by Begell House, Inc.