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 α‐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. Hum Mutat 26(4), 298–302, 2005. © 2005 Wiley‐Liss, Inc.

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   |texte=   A protein‐truncating mutation in CYP17A1 in three sisters with early‐onset breast cancer
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