Colon tumor
Molecular pathways
Microsatellite instability pathway

Topic Completed: 1 September 2010

Revised: 13 June 2019

Copyright: 2003-2019,, Inc.

PubMed Search: "Microsatellite instability pathway"

Shilpa Jain, M.D.
Page views in 2018: 1,916
Page views in 2019 to date: 2,149
Cite this page: Jain S. Microsatellite instability pathway. website. Accessed December 5th, 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
  • 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 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)
  • Differentiate by BRAF - mutations present in about 40 - 50% of sporadic MSI-H tumors but absent in Lynch syndrome; this has implications in follow up (Arch Pathol Lab Med 2011;135:578)
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)
Gross description
  • Usually right sided, expansive growth
Microscopic (histologic) description
  • Includes medullary, mucinous and signet ring cell carcinoma subtypes (Am J Surg Pathol 2003;27:1393)
  • Tumor infiltrating lymphocytes, peritumoral lymphocytes, no dirty necrosis; may be associated with serrated adenomas
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