Stains & CD markers
MSH6
Copyright: 2002-2025, PathologyOutlines.com, Inc.
PubMed Search: MSH6
MSH6
Author: Rebecca Obeng, M.D.
Last author update: 1 December 2016
Last staff update: 11 September 2023
Copyright: 2002-2025, PathologyOutlines.com, Inc.
PubMed Search: MSH6
Table of Contents
Definition / general | Essential features | Terminology | Epidemiology | Sites | Pathophysiology | Etiology | Diagnosis | Prognostic factors | Case reports | Treatment | Microscopic (histologic) description | Microscopic (histologic) images | Molecular / cytogenetics descriptionCite this page: Obeng R. MSH6. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/stainsmsh6.html. Accessed January 21st, 2025.
Definition / general
- The MSH6 gene on chromosome 2 is part of the DNA mismatch repair system
- It encodes a component of the MutS family of proteins that are involved in DNA mismatch repair, and heterodimerizes with MSH2 to form the MutS alpha complex, which serves as a bidirectional molecular switch for the mismatch repair machinery
Essential features
- Mutations in MSH6 are associated with increased risk of colorectal cancer, hereditary nonpolyposis colon cancer, Lynch syndrome and endometrial cancer
- Generally lead to milder microsatellite instability
- More commonly associated with distal colorectal cancer and endometrial cancer (Hum Mol Genet 2002;11;1303, Gastroenterology 2008;135:419)
- MSH6 expression can be reduced by chemotherapy and radiation (Am J Surg Pathol 2010;34:1798)
Terminology
- DNA mismatch repair protein Msh6, HNPCC5, HSAP, MutS homolog 6 (E. coli), G / T binding protein
Epidemiology
- Colorectal cancer in patients with Lynch syndrome:
- MSH6 mutations are associated with 22% - 69% risk in males and 10% - 61% risk in females (Exp Rev Mol Diagnostics 2016;16:591)
- Endometrial cancer:
- MSH6 mutations related to endometrial cancer are generally seen in older patients (Cancer Res 2006;66:7810; J Med Genet 2001;38:318)
- MSH6 mutation has 44% increased risk of endometrial cancer (J Natl Cancer Inst 2010;102:193)
Sites
- Ubiquitous nuclear expression in normal tissues
Pathophysiology
- Genetic alterations in MSH6 contribute to DNA mismatch repair deficiency that leads to microsatellite instability and increased risk of cancer
- MSH6 protein expression is unstable in absence of MSH2
- Loss of expression of MSH2 due to mutations usually results in the loss of expression of MSH6 (Adv Anat Pathol 2009;16:405; Exp Rev Mol Diagnostics 2016;16:591)
Etiology
- Germline or sporadic mutations in MHSH6 lead to microsatellite instability
Diagnosis
- Screening: immunohistochemical (IHC) stain; loss of nuclear staining suggests microsatellite instability
- Negative staining of MSH6 is usually due to mutations in MSH2 and should therefore raise suspicion for germline mutations (Cancer Treat Rev 2016;51:19)
- Missense and point mutations that lead to nonfunctional proteins can result in false negatives on IHC
- Confirmatory: molecular studies (PCR for microsatellite instability)
- High (MSI-H): at least 2 of 5 unstable markers or greater than or equal to 30% of unstable markers
- Low (MSI-L): one of five unstable markers or less than 30% of unstable markers
Prognostic factors
- Microsatellite instability resulting from mutations in MSH6 or other proteins involved in DNA mismatch repair is associated with better prognosis in comparison with microsatellite stable colorectal cancers (Ann Surg 1998;227:51; Clin Cancer Res 2005;11:8332; Ann Oncol 2013;24:1274; Cancer Epidemiol Biomarkers Prev 2001;10:917)
Case reports
- 15 year old girl with rectal cancer, with a novel MLH1 and MSH6 biallelic inheritance (Int J Colorectal Dis 2015;30:435)
- 46 year old woman with early onset endometrial cancer, with mutations in BRCA1 and MSH6 (BMC Cancer 2012;12:531)
Treatment
- Anti-PD-1 pathway blockade therapy for mismatch repair deficient colorectal cancers are in clinical trials with some showing significant objective response (Mod pathol 2009;22:1186; Clin Cancer Res 2013;19:462; N Engl J Med 2015;372:2509)
Microscopic (histologic) description
- Normal staining pattern: nuclear
- Cytoplasmic staining is abnormal and should not be misinterpreted as normal staining
Microscopic (histologic) images
Contributed by Epitomics
Colon, normal histology epithelium
Molecular / cytogenetics description
- National Cancer Institute recommendations: 5 microsatellite markers (BAT25, BAT26, N2S123, N5S346 and D17S250) for sequencing (Cancer Res 1998;58:5248) (additional markers may be used, however, there is no consensus on which markers to use)
- Sanger sequencing for germline mutations
- Multiplex ligation dependent probe amplification for large copy number variant detection
- Next generation sequencing may also be useful
