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

John L. Hopper, Vanessa M. Hayes, Amanda B. Spurdle, Georgia Chenevix-Trench, Mark A. Jenkins, Roger L. Milne, Gillian S. Dite, Andrea A. Tesoriero, Margaret R.E. McCredie, Graham G. Giles, Melissa C. Southey

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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 CYPl7A1 -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.

Original languageEnglish
Pages (from-to)298-302
Number of pages5
JournalHuman Mutation
Issue number4
Publication statusPublished - 1 Oct 2005
Externally publishedYes


  • Breast cancer susceptibility genes
  • Case-control-family study
  • CYPJ7
  • Early-onset breast cancer
  • Penetrance
  • Protein-truncating mutation
  • Segregation analysis

Cite this

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. E., Giles, G. G., & Southey, M. C. (2005). A protein-truncating mutation in CYP17A1 in three sisters with early-onset breast cancer. Human Mutation, 26(4), 298-302. https://doi.org/10.1002/humu.20237