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

Hum Mutat. 2005 Oct;26(4):298-302. doi: 10.1002/humu.20237.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Age of Onset
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Case-Control Studies
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Middle Aged
  • Mutation*
  • Polymorphism, Genetic
  • Population / genetics
  • Risk Factors
  • Siblings
  • Steroid 17-alpha-Hydroxylase / genetics*
  • Steroid 17-alpha-Hydroxylase / metabolism


  • CYP17A1 protein, human
  • Steroid 17-alpha-Hydroxylase

Associated data

  • OMIM/609300