Founding mutations and Alu-mediated recombination in hereditary colon cancer (original) (raw)

Nature Medicine volume 1, pages 1203–1206 (1995)Cite this article

Abstract

By screening members of Finnish families displaying hereditary nonpolyposis colorectal cancer (HNPCC) for predisposing germline mutations in MSH2 and MLH1, we show that two mutations in MLH1 together account for 63% (19/30) of kindreds meeting international diagnostic criteria. Mutation 1, originally detected as a 165-base pair deletion in MLH1 cDNA comprising exon 16, was shown to consist of a 3.5-kilobase genomic deletion most likely resulting from Alu-mediated recombination. Mutation 2 destroys the splice acceptor site of exon 6. A simple diagnostic test based on polymerase chain reaction was designed for both mutations. Our results show that these two ancestral founding mutations account for a majority of Finnish HNPCC kindreds and represent the first report of Alu-mediated recombination causing a prevalent, dominantly inherited predisposition to cancer.

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Authors and Affiliations

  1. Department of Medical Genetics, University of Helsinki, P. O. Box 21, (Haartmaninkatu 3), FIN-00014, Finland
    Minna Nyström-Lahti, Paula Kristo, Lauri A. Aaltonen, Anu-Liisa Moisio, Albert De La Chapelle & Päivi Peltomäki
  2. The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, Maryland, 21231, USA
    Nicholas C. Nicolaides, Kenneth W. Kinzler & Bert Vogelstein
  3. Roche Molecular Systems, Inc., 1145 Atlantic Avenue, Alameda, California, 94501, USA
    Sheng-Yung Chang
  4. Second Department of Surgery, Helsinki University Central Hospital, Haartmaninkatu 4, FIN-00290, Helsinki, Finland
    Heikki J. Järvinen
  5. Jyväskylä Central Hospital, FIN-40620, Jyväskylä, Finland
    Jukka-Pekka Mecklin
  6. Howard Hughes Medical Institute, 424 North Bond Street, Baltimore, Maryland, 21231, USA
    Bert Vogelstein

Authors

  1. Minna Nyström-Lahti
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  2. Paula Kristo
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  3. Nicholas C. Nicolaides
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  4. Sheng-Yung Chang
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  5. Lauri A. Aaltonen
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  6. Anu-Liisa Moisio
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  7. Heikki J. Järvinen
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  8. Jukka-Pekka Mecklin
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  9. Kenneth W. Kinzler
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  10. Bert Vogelstein
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  11. Albert De La Chapelle
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  12. Päivi Peltomäki
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Nyström-Lahti, M., Kristo, P., Nicolaides, N. et al. Founding mutations and Alu-mediated recombination in hereditary colon cancer.Nat Med 1, 1203–1206 (1995). https://doi.org/10.1038/nm1195-1203

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