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First description of mutational analysis of MLH1, MSH2 and MSH6 in Algerian families with suspected Lynch syndrome

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Abstract

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer (CRC) linked to germline defects in Mismatch Repair (MMR) genes. We present here, the first molecular study of the correlation between CRC and mutations occurring in these genes performed in twenty-one unrelated Algerian families. The presence of germline mutations in MMR genes, MLH1, MSH2 and MSH6 genes was tested by sequencing all exons plus adjacent intronic sequences and Multiplex ligand-dependent probe amplification (MLPA) for testing large genomic rearrangements. Pathogenic mutations were identified in 20 % of families with clinical suspicion on HNPCC. Two novel variants described for the first time in Algerian families were identified in MLH1, c.881_884delTCAGinsCATTCCT and a large deletion in MSH6 gene from a young onset of CRC. Moreover, the variants of MSH2 gene: c.942+3A>T, c.1030C>T, the most described ones, were also detected in Algerian families. Furthermore, the families HNPCC caused by MSH6 germline mutation may show an age of onset that is comparable to this of patients with MLH1 and MSH2 mutations. In this study, we confirmed that MSH2, MLH1, and MSH6 contribute to CRC susceptibility. This work represents the implementation of a diagnostic algorithm for the identification of Lynch syndrome patients in Algerian families.

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Acknowledgments

We are grateful to the members of the HNPCC families for their willingness to participate in this study and for, providing the blood samples. We thank Mr. Eric Clauser, Mr. Nadim Hamzaoui, Dr.Marie-Odile North, Mrs. Michèle Nigou and Mrs. Magalie Dambrun, members of Oncogenetic Laboratory, Cochin, Paris for their precious collaboration and excellent technical assistance and all members of the Biology and Genetics Laboratory, Medical Oncology service, University Hospital Center, Constantine, Algeria. We thank Dr. Zitouni Mina, Genomics and Biotechnology, Canada for reading and editing this work.

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Authors and Affiliations

  1. Department of Animal Biology, Faculty of Natural and Life Science, University 1, Mentouri Brothers, Constantine, Algeria

    H. Ziada-Bouchaar & D. Satta

  2. Laboratory of Biology and Molecular Genetics, Faculty of Medicine, University 3, Rabah Bitat, Constantine, Algeria

    H. Ziada-Bouchaar, K. Sifi, T. Filali, T. Hammada, D. Satta & N. Abadi

  3. Medical Oncology Service, University Hospital Center, Benbadis, Constantine, Algeria

    T. Filali

  4. Gastroenterology Service, University Hospital Center, Benbadis, Constantine, Algeria

    T. Hammada

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  1. H. Ziada-Bouchaar
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Correspondence to H. Ziada-Bouchaar.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Ziada-Bouchaar, H., Sifi, K., Filali, T. et al. First description of mutational analysis of MLH1, MSH2 and MSH6 in Algerian families with suspected Lynch syndrome. Familial Cancer 16, 57–66 (2017). https://doi.org/10.1007/s10689-016-9917-1

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