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Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals

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Abstract

Lynch syndrome (LS) is an autosomal dominant syndrome that predisposes individuals to development of cancers early in life. These cancers are mainly the following: colorectal, endometrial, ovarian, small intestine, stomach and urinary tract cancers. LS is caused by germline mutations in DNA mismatch repair genes (MMR), mostly MLH1 and MSH2, which are responsible for more than 85% of known germline mutations. To search for germline mutations in MLH1 and MSH2 genes in 123 unrelated South American suspected LS patients (Bethesda or Amsterdam Criteria) DNA was obtained from peripheral blood, and PCR was performed followed by direct sequencing in both directions of all exons and intron–exon junctions regions of the MLH1 and MSH2 genes. MLH1 or MSH2 pathogenic mutations were found in 28.45% (34/123) of the individuals, where 25/57 (43.85%) fulfilled Amsterdam I, II and 9/66 (13.63%) the Bethesda criteria. The mutations found in both genes were as follows: nonsense (35.3%), frameshift (26.47%), splicing (23.52%), and missense (9%). Thirteen alterations (35.14%) were described for the first time. The data reported in this study add new information about MLH1 and MSH2 gene mutations and contribute to better characterize LS in Brazil, Uruguay and Argentina. The high rate of novel mutations demonstrates the importance of defining MLH1 and MSH2 mutations in distinct LS populations.

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Acknowledgements

We thank Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP - 05/05155-6) and Instituto Nacional de Ciência e Tecnologia em Oncogenômica (INCITO - 2008/57887-9) for financial support.

Conflicts of interest

We have no competing interests.

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Authors and Affiliations

  1. Laboratory of Genomics and Molecular Biology, Centro Internacional de Pesquisa e Ensino (CIPE), A.C.Camargo Hospital, São Paulo, Brazil

    Mev Dominguez Valentin, Felipe Carneiro da Silva, Bianca Garcia Lisboa, Ligia Petrolini de Oliveira, Israel Gomy & Dirce Maria Carraro

  2. MsC/PhD Program, A.C.Camargo Hospital, São Paulo, Brazil

    Erika Maria Monteiro dos Santos, Fabio de Oliveira Ferreira, Wilson Toshihiko Nakagawa, Samuel Aguiar Junior & Benedito Mauro Rossi

  3. Coloproctology Department, Hospital Italiano, Buenos Aires, Argentina

    Mariana Redal

  4. Director of Hereditary Cancer Program, Hospital Italiano, Buenos Aires, Argentina

    Carlos Vaccaro

  5. Hospital de las Fuerzas Armadas, Montevideo, Uruguay

    Adriana Della Valle & Carlos Sarroca

  6. Department of Oncology, Clinical Sciences, Lund University, Barngatan 2B, 221 85, Lund, Sweden

    Mev Dominguez Valentin

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  1. Mev Dominguez Valentin
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  2. Felipe Carneiro da Silva
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Correspondence to Mev Dominguez Valentin.

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Valentin, M.D., Silva, F.C.d., Santos, E.M.M.d. et al. Characterization of germline mutations of MLH1 and MSH2 in unrelated south American suspected Lynch syndrome individuals. Familial Cancer 10, 641–647 (2011). https://doi.org/10.1007/s10689-011-9461-y

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