Hereditary non–polyposis colorectal cancer (HNPCC) is an autosomal dominant disorder characterized by the early onset of colorectal cancer and linked to germline defects in at least four mismatch repair genes. Although much has been learned about the molecular pathogenesis of this disease, questions related to effective presymptomatic diagnosis are largely unanswered because of its genetic complexity. In this study, we evaluated tumors from 74 HNPCC kindreds for genomic instability characteristic of a mismatch repair deficiency and found such instability in 92% of the kindreds. The entire coding regions of the five known human mismatch repair genes were evaluated in 48 kindreds with instability, and mutations were identified in 70%. This study demonstrates that a combination of techniques can be used to genetically diagnose tumor susceptibility in the majority of HNPCC kindreds and lays the foundation for genetic testing of this relatively common disease.

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  1. The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, Maryland, 21231, USA

    • Bo Liu
    • , Ramon Parsons
    • , Nickolas Papadopoulos
    • , Nicholas C. Nicolaides
    • , Bert Vocelstein
    •  & Kenneth W. Kinzler
  2. Creighton University School of Medicine, Omaha, Nebraska, 68178, USA

    • Henry T. Lynch
    •  & Patrice Watson
  3. Department of Pathology, University of Auckland School of Medicine, Auckland, New Zealand

    • Jeremy R. Jass
  4. Western General Hospital, Crew Road, Edinburgh, EH4 2XU, UK

    • Malcolm Dunlop
  5. Cancer Research Campaign Laboratory, Department of Pathology, University Medical School, Edinburgh, EH8 9AG, UK

    • Andrew Wyllie
  6. Department of Medical Genetics, University of Helsinki, FIN-00014, Helsinki, Finland

    • Païvi Peltomäki
    •  & Albert De La Chapeele
  7. Department of Pathology and Oncology Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland, 21205, USA

    • Stanley R. Hamilton
  8. The Howard Hughes Medical Institute, the Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, Maryland, 21231, USA

    • Bert Vocelstein


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