An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC
Mutations in DNA mismatch repair genes underlie lynch syndrome (HNPCC). Lynch syndrome resulting from mutations in MSH6 is considered to be attenuated in comparison to that caused by mutations in MLH1 and MSH2, thus more likely to be under diagnosed. In this study we report of a common mutation in the MSH6 gene in Ashkenazi Jews. Genetic counseling and diagnostic work-up for HNPCC was conducted in families who attended the high risk clinic for inherited cancer. We identified the mutation c.3984_3987dup in the MSH6 gene in 19 members of four unrelated Ashkenazi families. This mutation results in truncation of the transcript and in loss of expression of the MSH6 protein in tumors. Tumor spectrum among carriers included colon, endometrial, gastric, ovarian, urinary, and breast cancer. All but one family qualified for the Bethesda guidelines and none fulfilled the Amsterdam Criteria. Members of one family also co-inherited the c.6174delT mutation in the BRCA2 gene. The c.3984_3987dup in the MSH6 gene is a mutation leading to HNPCC among Ashkenazi Jews. This is most probably a founder mutation. In contrast to the c.1906G>C founder mutation in the MSH2 gene, tumors tend to occur later in life, and none of the families qualified for the Amsterdam criteria. c.3984_3987dup is responsible for 1/6 of the mutations identified among Ashkenazi HNPCC families in our cohort. Both mutations: c.3984_3987dup and c.1906G>C account for 61% of HNPCC Ashkenazi families in this cohort. These findings are of great importance for counseling, diagnosis, management and surveillance for Ashkenazi families with Lynch syndrome.
KeywordsHNPCC BRCA MSH6 Founder Ashkenazi MMR
Denaturing high performance liquid chromatography
Hereditary breast ovarian cancer
Hereditary non-polyposis colorectal cancer
This work was supported, in part, by the Israeli Cancer Association.
- 2.Banjerjee SK, Maldisi WF, Weston AP et al (1995) Microwave-based DNA extraction from paraffin-embedded tissue for PCR amplification. BioTechniques 18:768–773Google Scholar
- 7.Goldberg Y, Porat RM, Kedar I, Shochat C, Sagi M, Eilat A, Mendelson S, Hamburger T, Nissan A, Hubert A, Kadouri L, Pikarski E, Lerer I, Abeliovich D, Bercovich D, Peretz T (2008) Mutation spectrum in HNPCC in the Israeli population. Fam CancerGoogle Scholar
- 13.Nilbert M, Wikman FP, Hansen TV, Krarup HB, Orntoft TF, Nielsen FC, Sunde L, Gerdes AM, Cruger D, Timshel S, Bisgaard ML, Bernstein I, Okkels H (2008) Major contribution from recurrent alterations and MSH6 mutations in the Danish Lynch syndrome population. Fam CancerGoogle Scholar
- 19.Thiffault I, Hamel N, Pal T, McVety S, Marcus VA, Farber D, Cowie S, Deschênes J, Meschino W, Odefrey F, Goldgar D, Graham T, Narod S, Watters AK, MacNamara E, Du Sart D, Chong G, Foulkes WD (2004) Germline truncating mutations in both MSH2 and BRCA2 in a single kindred. Br J Cancer 90(2):483–491CrossRefPubMedGoogle Scholar
- 20.Toledano H, Goldberg Y, Kedar-Barnes I, Baris H, Porat RM, Shochat C, Bercovich D, Pikarsky E, Lerer I, Yaniv I, Abeliovich D, Peretz T (2008) Homozygosity of MSH2 c.1906G–>C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. Fam CancerGoogle Scholar