Inherited Cancer Syndromes • Molecular Genetics MSH6, Deletion/Duplication

Lynch syndrome (also known as Hereditary Non-Polyposis Colon Cancer, HNPCC), is an autosomal dominant hereditary cancer syndrome that accounts for 3-5% of all colon cancers.  Lynch syndrome-associated tumors are characterized by microsatellite instability (MSI) and are caused by germline mutations in any of four mismatch repair (MMR) genes (MLH1, MSH6, MSH2, PMS2).  The risk of colon and gastric cancers are increased in both sexes, and women with Lynch syndrome have an increased risk for endometrial and ovarian cancers. 

The testing strategy for Lynch syndrome includes screening by MSI analysis followed by immunohistochemistry (IHC) testing of MMR proteins.  Full gene sequencing and deletion/duplication analysis can then be performed to identify germline mutations in the putative mutated gene(s) identified by IHC. (Please contact Client Services at (855) 535-1522 for more information regarding MSI and IHC testing). Germline mutations in MLH1 and MSH2 account for 90% of Lynch syndrome cases while mutations of MSH6 and PMS2 comprise the remaining fractions. While one study indicated that 65% of MSH2 and 87% of MLH1 variants were point mutations (the rest being gross deletions/duplications), comprehensive clinical sensitivity of MSH2, MLH1, and MSH6 sequencing and deletion/duplication is unknown.

Reasons for Referral:

• Identification of inherited genetic defects in MMR gene(s) in colorectal cancer patients with tumors testing positive by IHC and/or MSI.
• Confirmation of a suspected diagnosis with a positive family history of early onset colon cancer when familial mutation is known.
• Predispositional testing for asymptomatic family members with a positive family history of colorectal cancer.

1. Balmaña J, Stockwell DH, Steyerberg EW, et al. Prediction of MLH1 and MSH2 Mutations in Lynch Syndrome. JAMA: The Journal of the American Medical Association. 2006;296(12):1469 -1478.
2. Bonadona, V. et al., 2011. Cancer Risks Associated With Germline Mutations in MLH1, MSH2, and MSH6 Genes in Lynch Syndrome. JAMA: The Journal of the American Medical Association, 305(22), pp.2304-2310.  
3. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group, 2009.  Recommendations from the EGAPP Working Group: genetic testing strategies in newly diagnosed individuals with colorectal cancer aimed at reducing morbidity and mortality from Lynch syndrome in relatives. Genetics in Medicine, 11(1), pp.35-41.
4. Goodfellow, P.J. et al., 2003. Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proceedings of the National Academy of Sciences, 100(10), pp.5908-5913.