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microsatellite instability

Instability in VNTR? Originally studied to identify loss of heterozygosity. Epidemiology: - 3% of colorectal cancer & endometrial cancers are associated with Lynch syndrome. Pathology: - microsatellite instability may occur as a result of dysfunction of DNA mismatch repair - microsatellite instability occurs in the germline of patients with hereditary nonpolyposis colorectal cancer (Lynch syndrome) & in 15% of sporadic colorectal cancers - mismatch repair deficiency involving BAT25, BAT26 - microsatellite instability increases odds of Lynch syndrome [4] - only 1/2 of cancers with Lynch syndrome abnormalities are colorectal cancer or endometrial cancer [4] - other tumors associated with Lynch syndrome - prostate cancer, sarcomas, mesothelioma, adrenocortical carcinoma, ovarian germ-cell tumor small intestinal cancer, gastric cancer [4] Genetics: - repetitive sequences of DNA - relatively high rates of mutation - may contribute to the rapid evolution of species-typical traits - alleles of repetitive polymorphic microsatellites in the 5' region of a gene may serve regulatory functions & confer individual differences in gene expression & may contribute to normal variation in behavioral traits [1] Management: - for patients with colorectal cancer, microsatellite instability correlates with longer recurrence-free survival after surgical resection with or without adjuvant chemotherapy [2] - pembrolizumab (Keytruda) FDA-approved for treatment of any unresectable or metastatic tumor with microsatellite instability [3]

Related

DNA mismatch repair; post-replication repair; DNA loop repair microsatellite or variable number of tandem repeat (VNTR)

General

chromosomal instability molecular diagnostic test

References

  1. Journal Watch 25(16):130, 2005 Hammock EA, Young LJ. Microsatellite instability generates diversity in brain and sociobehavioral traits. Science. 2005 Jun 10;308(5728):1630-4. PMID: 15947188
  2. Kim GP, Colangelo LH, Wieand HS, Paik S, Kirsch IR, Wolmark N, Allegra CJ; National Cancer Institute. Prognostic and predictive roles of high-degree microsatellite instability in colon cancer: a National Cancer Institute-National Surgical Adjuvant Breast and Bowel Project Collaborative Study. J Clin Oncol. 2007 Mar 1;25(7):767-72. Epub 2007 Jan 16. PMID: 17228023
  3. Bankhead C FDA Breaks New Ground with Expanded Keytruda Indication - Pembrolizumab for genetic defect, not tumor type. MedPage Today. May 23, 2017 https://www.medpagetoday.com/PublicHealthPolicy/FDAGeneral/65530
  4. Bankhead C More Cancers Seem to Harbor Lynch Syndrome Broader testing implied by 'practice-changing' study. MedPage Today. June 03, 2018 https://www.medpagetoday.com/meetingcoverage/asco/73245 - Schwark AL, et al Pan-cancer microsatellite instability predicts for presence of Lynch syndrome. American Society of Clinical Oncology (ASCO) 2018; Abstract LBA1509