Nature Genetics
17, 79 - 83 (1997)
doi:10.1038/ng0997-79
Familial colorectal cancer in Ashkenazim due to a hypermutable tract in APCSteven J. Laken1, Gloria M. Petersen1, 2, Stephen B. Gruber1, Carole Oddoux3, Harry Ostrer3, Francis M. Giardiello4, Stanley R. Hamilton1, 5, Heather Hampel6, Arnold Markowitz7, David Klimstra8, Suresh Jhanwar9, Sidney Winawer7, Kenneth Offit6, Michael C. Luce10, Kenneth W. Kinzler1
& Bert Vogelstein1, 11, 12
1The Johns Hopkins Oncology Center, 424 North Bond Street, Baltimore, Maryland 21231, USA.
2Department of Epidemiology, Johns Hopkins School of Public Health, 615 North Wolfe Street, Baltimore, Maryland 21205, USA.
3Human Genetics Program, Department of Pediatrics, New York University Medical Center, New York, New York 10016, USA.
4The Johns Hopkins Hospital, 935Blalock, 600North WolfeStreet, Baltimore, Maryland 21287, USA.
5Department of Pathology, Johns Hopkins Hospital, University School of Medicine, 720 Rutland Avenue, Baltimore, Maryland 21205, USA.
6Clinical Genetics Service, Department of Human Genetics, Memorial Sloan-Kettering Cancer Center (MSKCC), New York, New York 10021, USA.
7Gastroenterology and Nutrition Service, Department of Medicine, MSKCC, New York, New York 10021, USA.
8Surgical Pathology Service, Department of Pathology, MSKCC, New York, New York 10021, USA.
9Cytogenetics Service, Department of Human Genetics, MSKCC, New York, New York 10021, USA.
10Laboratory Corporation of America, Research Triangle Park, North Carolina 27709, USA.
11The Howard Hughes Medical Institute, Baltimore, Maryland 21231, USA.
Correspondence should be addressed to B.V.
Approximately 130,000 cases of col ore eta I cancer (CRC) are diagnosed in the United States each year1, and about 15% of these have a hereditary component2,3. Two well-defined syndromes, familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), account for up to 5% of the total new cases of CRC4. Truncating APC mutations are responsible for FAR5,6, and defective mismatch repair genes cause HNPCC4,7,8. However, the genes responsible for most of the familial cases are unknown. Here we report a mutation (T to A at APC nucleotide 3920) found in 6% of Ashkenazi Jews and about 28% of Ashkenazim with a family history of CRC. Rather than altering the function of the encoded protein, this mutation creates a small hypermutable region of the gene, indirectly causing cancer predisposition.
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