Microsatellite instability pathway

Colon tumor
Molecular pathways
Microsatellite instability pathway

Author: Shilpa Jain, M.D.

Topic Completed: 1 September 2010

Revised: 13 June 2019

Copyright: 2003-2019, PathologyOutlines.com, Inc.

PubMed Search: "Microsatellite instability pathway"

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Page views in 2019 to date: 1,794

Table of Contents

Cite this page: Jain S. Microsatellite instability pathway. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/colontumormolecularmicrosatellite.html. Accessed October 14th, 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)
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