MSH6 [BC19]

MSH6 is a heterodimer of MSH2 and binds to DNA containing G/T mismatches. The MSH2-MSH6 complex recognizes a single-based mispair insertion/deletion loop. An alteration of microsatellite repeats is the result of slippage owing to strand misalignment during DNA replication and is referred to as microsatellite instability (MSI) (1,2). These defects in DNA repair pathways have been related to human carcinogenesis. Studies have shown the mutations in MSH-1, MSH2, MSH6, and PMS2 genes contribute to the development of sporadic colorectal carcinoma. The repair of mismatch DNA is essential to maintaining the integrity of genetic information over time (1,2). Recently, a heterogeneous pattern of MSH6 expression was described in rare cases of colorectal, endometrial and sebaceous tumors (2). In this pattern, areas of strong MSH6 expression are juxtaposed with areas of complete loss of expression. Patients with colorectal carcinoma that is mismatch-repair-deficient and confirmed with immunohistochemistry (IHC) (MSH2/MSH6 negative or MLH1/PMS2 deleted) have shown objective response to PD-1 antibody, pembrolizumab (3). PD-L1 IHC test has been demonstrated to be a useful predictive marker for anti-PD-1 immunotherapy in colorectal carcinoma (4).

Specifications

1. Renkonen E, et al. Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. J Clin Oncol. 2003; 21:3629-37.
2. Graham RP, et al. Heterogenous MSH6 loss is a result of microsatellite instability within MSH6 and occurs in sporadic and hereditary colorectal and endometrial carcinomas. Am J Surg Pathol. 2015; 39:1370-6.
3. Lee LH, et al. Patterns and prognostic relevance of PD-1 and PD-L1 expression in colorectal carcinoma. Mod Pathol. 2016; 29:1333-42.
4. Le DI, et al. PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-20.
5. Center for Disease Control Manual. Guide: Safety Management, NO. CDC-22, Atlanta, GA. April 30, 1976 “Decontamination of Laboratory Sink Drains to Remove Azide Salts.”
6. Clinical and Laboratory Standards Institute (CLSI). Protection of Laboratory Workers from Occupationally Acquired Infections; Approved Guideline-Fourth Edition CLSI document M29-A4 Wayne, PA 2014.