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Genetic Heterogeneity among Fanconi Anemia Heterozygotes and Risk of Cancer

¹ Cancer Research and Treatment Center/Internal Medicine, University of New Mexico, Albuquerque, New Mexico; ² Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center; ³ Laboratory for Human Genetics and Hematology, The Rockefeller University, New York, New York; ⁴ Department of Human Genetics, University of Wurzburg, Wurzburg, Germany; and ⁵ Department of Pediatric Oncology, Hematology and Immunology, University of Dusseldorf, Dusseldorf, Germany

Requests for reprints: Arleen D. Auerbach, Laboratory of Human Genetics and Hematology, The Rockefeller University, 1230 York Avenue, Box 77, New York, NY 10021-6399. Phone: 212-327-7533; Fax: 212-327-8262; E-mail: auerbac{at}mail.rockefeller.edu.

Fanconi anemia (FA) is a rare autosomal recessive disease characterized by a greatly increased risk of cancer among those diagnosed with the syndrome. The question as to whether FA heterozygotes are at increased risk for cancer is of great importance to those at risk for being a carrier. To address this question, we formed a cohort of grandparents of probands identified through the International Fanconi Anemia Registry. We obtained informed consent, a short questionnaire, and either blood or buccal swab DNA. After diagnosis of the proband was confirmed and complementation studies or DNA sequencing on the proband were completed, mutation analyses of the putative carriers and noncarriers was carried out. Standardized incidence ratios (SIR) were calculated to compare the observed cancer incidence of the grandparents and other relatives with the expected rates of cancer, using the Surveillance, Epidemiology, and End Results registries and the Connecticut Cancer registry. In the 944 study subjects who participated (784 grandparents and 160 other relatives), there was no suggestion of an increase in overall cancer incidence. On the other hand, a significantly higher rate of breast cancer than expected was observed among carrier grandmothers [SIR, 1.7; 95% confidence interval (95% CI), 1.1–2.7]. Among the grandmothers, those who were carriers of FANCC mutations were found to be at highest risk (SIR, 2.4; 95% CI, 1.1–5.2). Overall, there was no increased risk for cancer among FA heterozygotes in this study of Fanconi relatives, although there is some evidence that FANCC mutations are possibly breast cancer susceptibility alleles. [Cancer Res 2007;67(19):9591–6]

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