Microsatellite instability pathway
Reviewers: Shilpa Jain, M.D, New York University (see Reviewers page)
Revised: 31 October 2010, last major update September 2010
Copyright: (c) 2003-2010, PathologyOutlines.com, Inc.
● Microsatellites, also called short tandem repeats, are repeating sequences of 1-6 base pairs of DNA (Wikipedia)
● Microsatellite instability is characterized by widespread alteration in the size of repetitive DNA sequences caused by defective DNA mismatch repair
● Have high (MSI-H) or low levels of instability (MSI-L)
● Seen in 10-15% of sporadic carcinomas and hereditary nonpolyposis colon cancer (Gut Liver 2010;4:151)
● Due to either germline mutations (Lynch syndrome and variants) or sporadic due to promotion methylation
● Due to alterations in mismatch repair genes MSH2, MSH6, MLH1, PMS2 and mitotic checkpoint regulator genes whose alterations cause gross chromosomal abnormalities (BUB1, BUBR1, CDC4, Cancer Metastasis Rev 2004;23:11)
● Inactivation of both alleles of nucleotide mismatch repair, usually hMSH2 or hMLH1, promotes tumorigenesis
● Tumors have numerous nucleotide substitutions and insertion/deletion mutations in microsatellites, but normal total DNA content and relatively normal cytogenetics with only infrequent allelic gains/losses
● Sporadic MSI-H cases arise predominantly through promoter hypermethylation and silencing of the hMLH1 gene
● Herediatry MSI-H (hereditary non-polyposis colorectal cancer) typically has germline mutations in one of the DNA mismatch repair genes (Nat Genet 2006; 38(7):787-93)
● There may be different patterns of gene mutations in distal colon/rectum from proximal colon (BMC Cancer 2010;10:587)
● Often present at earlier stage than other colon carcinomas
● Tumors with MSI-H tend to be more proximally located, poorly differentiated, with mucinous histology and prominent lymphocytic infiltration, and have been linked with TGFBRII and BRAF mutation (J Clin Pathol 2008;61:561)
● Frequently present in colon/stomach double primaries (Mod Pathol 2001;14:543)
● Although the prognosis is stage and grade dependent, tumors with identical morphological features display considerable heterogeneity in clinical outcome
● Patients with MSI-H have a stage-independent improved survival compared to patients with microsatellite stable (MSS) tumors in most, though not all studies, but do not benefit from treatment with 5-fluorouracil in randomized adjuvant therapy trials (N Engl J Med 2003;349:247)
● Includes medullary, mucinous and signet ring carcinoma subtypes (Am J Surg Pathol 2003;27:1393)
End of Colon tumor > Molecular pathways > Microsatellite instability pathway
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