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Aberrant splicing caused by a MLH1 splice donor site mutation found in a young Japanese patient with Lynch syndrome

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Abstract

Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, characterized by predisposition to colorectal cancer and other associated cancers, is an autosomal-dominant disorder mainly caused by germline mutations in DNA mismatch repair (MMR) genes such as MLH1, MSH2, and MSH6. Some mutations that disrupt splice donor or acceptor sites cause aberrant mRNA splicing. These mutations are generally considered as pathogenic ones, however, it is sometimes uneasy to accurately predict their pathogenicity without functional assays, particularly when the mutation is a single nucleotide substitution. In this report, we describe a 25-year-old patient with Lynch syndrome who carries a germline variant in a splice donor site of the MLH1 gene (c.790 + 5 G > T), which was first detected among Asian populations. The immunohistochemical analysis revealed loss of MLH1 protein expression in the tumor. Our splicing assay confirmed that the intronic MLH1 variant actually caused aberrant splicing, supporting its pathogenic effect. Our data accumulate more information on the genotype-phenotype relationships in patients with Lynch syndrome.

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Acknowledgments

This study was supported in part by Ministry of Education, Science, Sports and Culture.

Conflict of Interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Department of Clinical Oncology, Institute of Development, Aging and Cancer, and Tohoku University Hospital, Tohoku University, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Masanobu Takahashi, Hideki Shimodaira & Chikashi Ishioka

  2. Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan

    Yoichi Furukawa & Yusuke Nakamura

  3. Department of Clinical Oncology, Miyagi Cancer Center, Medeshima Shiote Aza Nodayama 47-1, Natori, Miyagi, 981-1293, Japan

    Masato Sakayori

  4. Department of Pathology, Tohoku University School of Medicine and Tohoku University Hospital, 1-1 Seiryo-machi, Aoba-ku, Sendai, 980-8574, Japan

    Takuya Moriya

  5. Division of Colorectal Surgery, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan

    Yoshihiro Moriya

Authors
  1. Masanobu Takahashi
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  2. Yoichi Furukawa
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  3. Hideki Shimodaira
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  4. Masato Sakayori
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  5. Takuya Moriya
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  6. Yoshihiro Moriya
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  7. Yusuke Nakamura
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  8. Chikashi Ishioka
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Corresponding author

Correspondence to Chikashi Ishioka.

Additional information

This study is contacted for HNPCC registry and genetic testing project of the Japanese Society for Cancer of the Colon and Rectum (JSCCR).

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Takahashi, M., Furukawa, Y., Shimodaira, H. et al. Aberrant splicing caused by a MLH1 splice donor site mutation found in a young Japanese patient with Lynch syndrome. Familial Cancer 11, 559–564 (2012). https://doi.org/10.1007/s10689-012-9547-1

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  • DOI: https://doi.org/10.1007/s10689-012-9547-1

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