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N-acetyltransferase 2 Influences Cancer Prevalence in hMLH1/hMSH2 Mutation Carriers¹

Research Group Human Genetics, University Hospital, 4031 Basel, and Department of Medical Genetics, University Children’s Hospital, 4058 Basel, Switzerland [K. H., W. W., Hj. M., Z. D.]; Hunter Area Pathology Service, John Hunter Hospital, University of Newcastle, 2305 Australia [R. J. S.]; Unit of Identification of Genetic Predisposition to Cancer, Division of Oncology, University Hospitals, 1211 Geneva, Switzerland [P. C.]; and Laboratoire d’ADN, Institut Central des Hôpitaux Valaisans, 1951 Sion, Switzerland [P. H.]

Hereditary nonpolyposis colorectal cancer (HNPCC), an inherited cancer predisposition syndrome, has been associated with germline mutations in DNA mismatch repair (MMR) genes. Because a deficiency in MMR does not predict a specific cancer phenotype, modifying genes may account in part for the variation in disease expression. We determined the N-acetyltransferase 2 (NAT2) genotype in 26 unaffected and 52 cancer-affected hMLH1/hMSH2 mutation carriers coming from 21 Swiss HNPCC families. Slow acetylators were found to be significantly (P < 0.03) more prevalent in the group of affected mutation carriers. Our results suggest a protective effect of the NAT2 rapid acetylator phenotype, an observation that could have implications for genetic counseling and management of MMR gene mutation carriers.

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