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Mutational analysis of hMsh6 in Israeli HNPCC and HNPCC-like Families

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Abstract

Germline mutations in DNA mismatch repair (DNA-MMR) genes, mainly hMlh1 and hMsh2, underlie Hereditary Non-Polyposis Colorectal Cancer (HNPCC). Germline hMSH6 gene mutations have been reported in a small subset of HNPCC families. In the present study, ethnically diverse individuals with HNPCC and HNPCC-like features were genotyped for hMsh6 germline mutations using exon-specific PCR, DGGE, and DNA sequencing. The study encompassed 92 individuals representing 88 unrelated families who were previously analyzed for Msh2 and Mlh1 mutations: Jewish Ashkenazim (n = 44), non-Ashkenazim (n = 27), Israeli Moslem-Arab (n = 15), Druze (n=3), and Cypriot non-Jews (n = 3). Of the study population, 71 had colon cancer (CRC), mean age at diagnosis was 50.9±13.2 years (range16–73 years), 5 had endometrial cancer (two with concurrent CRC), (mean 43.6±3.26 years, range 38–45 years), and unaffected individuals (n = 18) were first degree relatives within HNPCC families and were genotyped at a mean age of 48.3±11.7 years (range 30–69 years). Of the 92 individuals analyzed, none showed a truncating hMsh6 mutation, and 6 (6.6%) harbored one of three germline missense mutations: a previously reported one (V878A), and two novel mutations (V509A, S227I). The pathogenic significance of these three missense mutations is yet unclear. In addition, 5 polymorphisms were detected, 2 of which were novel.

We conclude that the rate of pathogenic hMsh6 mutations in HNPCC families of Jewish and Mediterranean origin is low, and that mutations in other genes probably account for the phenotype in these families.

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Abbreviations

CRC:

colorectal cancer

DGGE:

denaturing gradient gel electrophoresis

DNA-MMR:

DNA mismatch repair

HNPCC:

hereditary non-polyposis colon cancer

MSI:

microsatellite instability

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Authors and Affiliations

  1. Head of the Susanne Levy Gertner Oncogenetics Unit, The Danek Gertner Institute of Genetics, Chaim Sheba Medical Center, Tel-Hashomer, 52621, Israel

    Shiri Dovrat, Zvi Fireman & Eitan Friedman

  2. The Institute of Gestroenterology, Chaim Sheba Medical Center, Tel-Hashomer, Israel

    Herma H. Fidder & Shimon Bar Meir

  3. The Oncology Institute, Elias Sourasky Medical Center, Tel-Aviv, Israel

    Arie Figer & Ravit Geva

  4. The Oncology Institute, Rabin Medical Center, Petach Tikvah, Israel

    Dov Flex

  5. The Sackler School of Medicine, Tel-Aviv University, Ramat Aviv, Israel

    Arie Figer, Herma H. Fidder, Dov Flex, Shimon Bar Meir & Eitan Friedman

  6. The Oncology Unit, Rivkah Sieff Medical Center, Zefat, Israel

    Jamal Zidan

  7. The Bruce Rappaport School of Medicine, the Technion, Haifa, Israel

    Zvi Fireman & Jamal Zidan

  8. The Mendel Center for Biomedical Sciences, Nicosia, Cyprus

    Pavlos Neophytou

Authors
  1. Shiri Dovrat
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  2. Arie Figer
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  10. Eitan Friedman
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Correspondence to Eitan Friedman.

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Dovrat, S., Figer, A., Fidder, H.H. et al. Mutational analysis of hMsh6 in Israeli HNPCC and HNPCC-like Families. Familial Cancer 4, 291–294 (2005). https://doi.org/10.1007/s10689-005-1255-7

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  • DOI: https://doi.org/10.1007/s10689-005-1255-7

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