Population-based estimate of prostate cancer risk for carriers of the HOXB13 missense mutation G84E

PLoS One. 2013;8(2):e54727. doi: 10.1371/journal.pone.0054727. Epub 2013 Feb 15.

Abstract

The HOXB13 missense mutation G84E (rs138213197) is associated with increased risk of prostate cancer, but the current estimate of increased risk has a wide confidence interval (width of 95% confidence interval (CI) >200-fold) so the point estimate of 20-fold increased risk could be misleading. Population-based family studies can be more informative for estimating risks for rare variants, therefore, we screened for mutations in an Australian population-based series of early-onset prostate cancer cases (probands). We found that 19 of 1,384 (1.4%) probands carried the missense mutation, and of these, six (32%) had a family history of prostate cancer. We tested the 22 relatives of carriers diagnosed from 1998 to 2008 for whom we had a DNA sample, and found seven more carriers and one obligate carrier. The age-specific incidence for carriers was estimated to be, on average, 16.4 (95% CI 2.5-107.2) times that for the population over the time frame when the relatives were at risk prior to baseline. We then estimated the age and birth year- specific cumulative risk of prostate cancer (penetrance) for carriers. For example, the penetrance for an unaffected male carrier born in 1950 was 19% (95% CI 5-46%) at age 60 years, 44% (95% CI 18-74%) at age 70 years and 60% (95% CI 30-85%) at age 80 years. Our study has provided a population-based estimate of the average risk of prostate cancer for HOXB13 missense mutation G84E carriers that can be used to guide clinical practice and research. This study has also shown that the majority of hereditary prostate cancers due to the HOXB13 missense mutation are 'sporadic' in the sense that unselected cases with the missense mutation do not typically report having a family history of prostate cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Australia / epidemiology
  • Homeodomain Proteins / genetics*
  • Humans
  • Incidence
  • Male
  • Middle Aged
  • Mutation, Missense*
  • Prostate / metabolism
  • Prostate / pathology
  • Prostatic Neoplasms / epidemiology
  • Prostatic Neoplasms / genetics*
  • Prostatic Neoplasms / pathology
  • Risk Factors

Substances

  • HOXB13 protein, human
  • Homeodomain Proteins

Supplementary concepts

  • Prostate cancer, familial

Grants and funding

The work was supported largely by infrastructure and core funding provided by Cancer Council Victoria. Additional support was provided by Tattersall's charitable programme, The Whitten Foundation, PricewaterhouseCoopers Australia charitable programme and by grants from the National Health and Medical Research Council. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.