Familial Cancer

, Volume 9, Issue 2, pp 141–150

An Ashkenazi founder mutation in the MSH6 gene leading to HNPCC

Authors

    • Sharret Institute of OncologyHadassah-Hebrew University Medical Center
  • Rinnat M. Porat
    • Department of PathologyHadassah-Hebrew University Medical Center
  • Inbal Kedar
    • The Raphael Recanati Genetics InstituteThe Rabin Medical Center
  • Chen Shochat
    • The Human Molecular Genetics & Pharmacogenetics LabMigal—Galilee Bio-Technology Center
  • Daliah Galinsky
    • Sharret Institute of OncologyHadassah-Hebrew University Medical Center
  • Tamar Hamburger
    • Sharret Institute of OncologyHadassah-Hebrew University Medical Center
  • Ayala Hubert
    • Sharret Institute of OncologyHadassah-Hebrew University Medical Center
  • Hana Strul
    • Department of GastroenterologyTASMC
  • Revital Kariiv
    • Department of GastroenterologyTASMC
  • Liat Ben-Avi
    • Department of Human GeneticsHadassah-Hebrew University Medical Center
  • Moran Savion
    • Department of Human GeneticsHadassah-Hebrew University Medical Center
  • Eli Pikarsky
    • Department of PathologyHadassah-Hebrew University Medical Center
  • Dvorah Abeliovich
    • Department of Human GeneticsHadassah-Hebrew University Medical Center
  • Dani Bercovich
    • The Human Molecular Genetics & Pharmacogenetics LabMigal—Galilee Bio-Technology Center
    • Tel Hai Academic College
  • Israela Lerer
    • Department of Human GeneticsHadassah-Hebrew University Medical Center
  • Tamar Peretz
    • Sharret Institute of OncologyHadassah-Hebrew University Medical Center
Article

DOI: 10.1007/s10689-009-9298-9

Cite this article as:
Goldberg, Y., Porat, R.M., Kedar, I. et al. Familial Cancer (2010) 9: 141. doi:10.1007/s10689-009-9298-9

Abstract

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.

Keywords

HNPCCBRCAMSH6FounderAshkenaziMMR

Abbreviations

AC

Amsterdam criteria

BC

Breast cancer

CRC

Colorectal cancer

DHPLC

Denaturing high performance liquid chromatography

HBOC

Hereditary breast ovarian cancer

HNPCC

Hereditary non-polyposis colorectal cancer

IHC

Immunohistochemistry

MMR

Mismatch repair

MSI

Microsatellite instability

Copyright information

© Springer Science+Business Media B.V. 2009