title: Genetic heterogeneity among Fanconi anemia heterozygotes and risk of cancer.
abstract: 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.
authors.affiliation: Cancer Research and Treatment Center/Internal Medicine, University of New Mexico, Albuquerque, New Mexico, USA.
authors.forename: Marianne
authors.initials: M
authors.lastname: Berwick
authors.forename: Jaya M
authors.initials: JM
authors.lastname: Satagopan
authors.forename: Leah
authors.initials: L
authors.lastname: Ben-Porat
authors.forename: Ann
authors.initials: A
authors.lastname: Carlson
authors.forename: Katherine
authors.initials: K
authors.lastname: Mah
authors.forename: Rashida
authors.initials: R
authors.lastname: Henry
authors.forename: Raffaella
authors.initials: R
authors.lastname: Diotti
authors.forename: Kelly
authors.initials: K
authors.lastname: Milton
authors.forename: Kanan
authors.initials: K
authors.lastname: Pujara
authors.forename: Tom
authors.initials: T
authors.lastname: Landers
authors.forename: Sat
authors.initials: S
authors.lastname: Dev Batish
authors.forename: José
authors.initials: J
authors.lastname: Morales
authors.forename: Detlev
authors.initials: D
authors.lastname: Schindler
authors.forename: Helmut
authors.initials: H
authors.lastname: Hanenberg
authors.forename: Robert
authors.initials: R
authors.lastname: Hromas
authors.forename: Orna
authors.initials: O
authors.lastname: Levran
authors.forename: Arleen D
authors.initials: AD
authors.lastname: Auerbach
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D005199:Fanconi Anemia / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D009369:Neoplasms / Q000235:genetics*