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Definition / general | Terminology | Epidemiology | Etiology | Clinical features | Prognostic factors | Microscopic (histologic) descriptionCite this page: Jain S. Microsatellite instability pathway. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/colontumormolecularmicrosatellite.html. Accessed April 23rd, 2019.
Definition / general
- Microsatellites, also called short tandem repeats, are repeating sequences of 1 - 6 base pairs of DNA (Wikipedia: Microsatellite [Accessed 8 August 2018])
- Microsatellite instability is characterized by widespread alteration in the size of repetitive DNA sequences caused by defective DNA mismatch repair
Terminology
- Have high (MSI-H) or low levels of instability (MSI-L)
Epidemiology
- Seen in 10 - 15% of sporadic carcinomas and hereditary nonpolyposis colon cancer (Gut Liver 2010;4:151)
Etiology
- 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 nonpolyposis colorectal cancer) typically has germline mutations in one of the DNA mismatch repair genes (Nat Genet. 2006;38:787)
- There may be different patterns of gene mutations in distal colon / rectum from proximal colon (BMC Cancer 2010;10:587)
Clinical features
- 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)
Prognostic factors
- 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)
Microscopic (histologic) description
- Includes medullary, mucinous and signet ring cell carcinoma subtypes (Am J Surg Pathol 2003;27:1393)
