title: A protein-truncating mutation in CYP17A1 in three sisters with early-onset breast cancer.
abstract: 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.
authors.affiliation: Centre for Genetic Epidemiology, The University of Melbourne, Carlton, Victoria, Australia. j.hopper@unimelb.edu.au
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.forename: Vanessa M
authors.initials: VM
authors.lastname: Hayes
authors.forename: Amanda B
authors.initials: AB
authors.lastname: Spurdle
authors.forename: Georgia
authors.initials: G
authors.lastname: Chenevix-Trench
authors.forename: Mark A
authors.initials: MA
authors.lastname: Jenkins
authors.forename: Roger L
authors.initials: RL
authors.lastname: Milne
authors.forename: Gillian S
authors.initials: GS
authors.lastname: Dite
authors.forename: Andrea A
authors.initials: AA
authors.lastname: Tesoriero
authors.forename: Margaret R E
authors.initials: MR
authors.lastname: McCredie
authors.forename: Graham G
authors.initials: GG
authors.lastname: Giles
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Southey
mesh_terms: D000328:Adult; D017668:Age of Onset; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D011110:Polymorphism, Genetic; D011153:Population / Q000235:genetics; D012307:Risk Factors; D035781:Siblings; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics* / Q000378:metabolism
chemical_list: C501892:CYP17A1 protein, human; D013254:Steroid 17-alpha-Hydroxylase