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A protein-truncating mutation in CYP17A1 in three sisters with early-onset breast cancer


The hormonal etiology of breast cancer is well-established. Many studies have assessed whether polymorphisms in steroid hormone metabolism genes are associated with breast cancer risk. We measured the CYP17A1 -34T>C (c.-34T>C) promoter polymorphism in a population-based study of 1,404 Australian women with breast cancer diagnosed before age 60 years (case probands), 1,903 relatives, and 788 controls. Within-family analyses suggested the CC genotype was associated with, on average, a small increased risk. This finding appeared to be influenced by the families of three early-onset case probands with multiple affected sisters. CYP17A1 mutation screening revealed a case proband diagnosed at age 38 years who had a germline protein-truncating mutation (c.775C>T, p.Arg239X), which results in a nonfunctional enzyme and has been reported in a male compound heterozygote with 17 alpha-hydroxylase deficiency. This mutation was carried by both sisters diagnosed with breast cancer at ages 34 and 42 years, but not by a 57-year-old unaffected sister. It was not found in any of the other tested case probands (48 with multiple-affected relatives and 241 randomly selected) or controls. This study suggests there may be rare mutations in steroid hormone metabolism genes associated with a high dominantly-inherited breast cancer risk, and demonstrates how ""high-risk susceptibility genes"" might be discovered using population-based case-control-family studies.

Type Journal
ISBN 1098-1004 (Electronic)
Authors Hopper, J. L.;Hayes, V. M.;Spurdle, A. B.;Chenevix-Trench, G.;Jenkins, M. A.;Milne, R. L.;Dite, G. S.;Tesoriero, A. A.;McCredie, M. R.;Giles, G. G.;Southey, M. C. :
Published Date 2005-01-01
Published Volume 26
Published Issue 4
Published Pages 298-302
Status Published in-print
URL link to publisher's version