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MSI-High Colorectal CA : Genetics

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Genetics of MSI-High Colorectal Cancers: Based on microsatellite instability (MSI) status, colorectal cancers (CRCs) can be subdivided into two broad groups: MSI-high and MSI stable or low.

MSI-H colorectal carcinomas are a heterogenous group of tumors and include HNPCC, right-sided sporadic CRC, and serrated adenocarcinomas; however, they show some distinct biologic characteristics when compared to CRCs with stable or low level of microsatellite instability.

MSI-High tumors make up about 15% of all colorectal carcinomas. They carry either germline mutation in one of the DNA mismatch repair genes (Lynch Syndrome; 3% of cases) or somatic inactivation of one of the genes (MLH1, MSH2, MSH6, & PMS2) in the pathway, most commonly through hypermethylation of MLH1 gene promoter (sporadic MSI-H; 12% of cases). Such cases are strongly associated with BRAF V600E mutation. In a small subset of MSI-H tumors, there are no mutations in MMR genes but there is overexpression of various miRNAs that may silence one of the MMR genes.

Impaired DNA mismatch repair causes a hypermutable state which gives rise to insertion and deletion mutations in short tandem repeats (microsatellites) as well as nucleotide substitutions throughout the genome. Whole-exome sequencing based studies of CRCs have shown >1700 somatic mutations per tumor in patients with MMR-deficient cancers as compared to <100 mutations per tumor in patients with DNA mismatch repair-proficient cancers.

This image of MSI-H colorectal carcinoma shows tumor cells arranged in anastomosing trabeculae and a few poorly-formed glands with small abortive lumens.

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