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Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing

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Abstract

Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is one of the commonest cancer susceptibility syndromes. It is characterized by early onset colon cancer and a variety of extracolonic tumours. Germline mutations in the DNA mismatch repair genes (MLH1, MSH2, MSH6, PMS1, and PMS2) are responsible for this disorder. Identifying an affected individual depends on the tumour histopathology, family history that fulfils the Amsterdam and/or Bethesda criteria, tumour immunohistochemistry, microsatellite instability, and finally molecular analysis of an affected member. It is a laborious, time consuming and expensive procedure, which needs the effort of a multi-disciplinary team. However, once the diagnosis is established and germline defect is identified, other high risk pre-symptomatic carriers could be offered intensive surveillance and management as a preventive measure against cancer development. Here, we present two large highly consanguineous HNPCC-families from Kuwait in whom a founder MSH2 mutation was identified. The relationship between this mutation and cancer expressivity in two large consanguineous families harbouring other genetic defects is discussed. Moreover, we shed light on the challenges pertaining to diagnosis, screening, premarital counselling of couples and prenatal diagnosis of offspring with biallelic MSH2 gene mutation.

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Abbreviations

CRC:

Colorectal cancer

HNPCC:

Hereditary non-polyposis colorectal cancer

ICH:

Immunohistochemistry

KMGC:

Kuwait Medical Genetics Centre

MMR:

Mismatch-repair

MSI:

Microsatellite instability

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Authors and Affiliations

  1. Kuwait Medical Genetics Centre, Maternity Hospital, P.O. Box: 5833, 13059, Safat, Kuwait

    Makia J. Marafie

  2. Kuwait Medical Genetics Centre, Maternity Hospital, P.O. Box: 31121, 80901, Sulaibikhat, Kuwait

    Sadiqa Al-Awadi, Fatemah Al-Mosawi & Alaa Elshafey

  3. Faculty of Medicine, Department of Pathology, Molecular Pathology Unit, Kuwait University, P.O. Box: 24923, Safat, Kuwait

    Waleed Al-Ali & Fahd Al-Mulla

Authors
  1. Makia J. Marafie
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  2. Sadiqa Al-Awadi
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  3. Fatemah Al-Mosawi
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  4. Alaa Elshafey
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  5. Waleed Al-Ali
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  6. Fahd Al-Mulla
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Correspondence to Makia J. Marafie.

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Marafie, M.J., Al-Awadi, S., Al-Mosawi, F. et al. Impact of 226C>T MSH2 gene mutation on cancer phenotypes in two HNPCC-associated highly-consanguineous families from Kuwait: emphasis on premarital genetic testing. Familial Cancer 8, 289–298 (2009). https://doi.org/10.1007/s10689-009-9275-3

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  • DOI: https://doi.org/10.1007/s10689-009-9275-3

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