Defective mismatch repair, microsatellite mutation bias, and variability in clinical cancer phenotypes.
Microsatellite instability is associated with 10% to 15% of colorectal, endometrial, ovarian, and gastric cancers, and has long been used as a diagnostic tool for hereditary nonpolyposis colorectal carcinoma-related cancers. Tumor-specific length alterations within microsatellites are generally accepted to be a consequence of strand slippage events during DNA replication, which are uncorrected due to a defective postreplication mismatch repair (MMR) system. Mutations arising within microsatellites associated with critical target genes are believed to play a causative role in the evolution of MMR-defective tumors. In this review, we summarize current evidence of mutational biases within microsatellites arising as a consequence of intrinsic DNA sequence effects as well as variation in MMR efficiency. Microsatellite mutational biases are generally not considered during clinical testing; however, we suggest that such biases may be clinically significant as a factor contributing to phenotypic variation among microsatellite instability-positive tumors.
Shah
Sandeep N
SN
Department of Pathology, Gittlen Cancer Research Foundation, Pennsylvania State University College of Medicine, Hershey, Pennsylvania 17033, USA.
Hile
Suzanne E
SE
Eckert
Kristin A
KA
D000818:Animals; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics / Q000473:pathology; D053843:DNA Mismatch Repair; D006801:Humans; D053842:Microsatellite Instability; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology