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Eur Urol. 2014 Jan;65(1):169-76. doi: 10.1016/j.eururo.2012.07.027. Epub 2012 Jul 20.

A population-based assessment of germline HOXB13 G84E mutation and prostate cancer risk.

Author information

1
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Electronic address: robert.karlsson@ki.se.

Abstract

BACKGROUND:

A rare but recurrent missense mutation (G84E, rs138213197) in the gene homeobox B13 (HOXB13) was recently reported to be associated with hereditary prostate cancer.

OBJECTIVE:

To explore the prevalence and penetrance of HOXB13 G84E in a general population.

DESIGN, SETTING, AND PARTICIPANTS:

G84E and 14 additional HOXB13 polymorphisms were genotyped in two population-based, Swedish, case-control samples (Cancer of the Prostate in Sweden [CAPS] and Stockholm-1) comprising 4693 controls and 5003 prostate cancer cases. CAPS collected data on patients and population controls nationally between 2001 and 2003. Stockholm-1 collected data on biopsy-positive patients and biopsy-negative controls in the Stockholm area between 2005 and 2007.

OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:

The outcome was pathologically verified prostate cancer. Relative and absolute risks among HOXB13 G84E mutation carriers were explored, as was the combined impact on disease risk of G84E and a polygenic score based on 33 established, common, low-risk variants.

RESULTS AND LIMITATIONS:

HOXB13 G84E was observed in 1.3% of population controls and was strongly associated with prostate cancer risk (CAPS: odds ratio [OR]: 3.4; 95% confidence interval [CI], 2.2-5.4; Stockholm-1: OR: 3.5; 95% CI, 2.4-5.2). The strongest association was observed for young-onset (OR: 8.6; 95% CI, 5.1-14.0) and hereditary (OR: 6.6; 95% CI, 3.3-12.0) prostate cancer. Haplotype analyses supported that G84E is a founder mutation. G84E carriers have an estimated 33% (95% CI, 23-46) cumulative risk to age 80 yr of prostate cancer, compared to 12% (95% CI, 11-13) among noncarriers. For G84E carriers within the top quartile of a polygenic score of established susceptibility variants, the cumulative risk was estimated at 48% (95% CI, 36-64).

CONCLUSIONS:

HOXB13 G84E is prevalent in >1% of the Swedish population and is associated with a 3.5-fold increased risk of prostate cancer. One-third of G84E carriers will be diagnosed with prostate cancer, which has implications for surveillance in mutation carriers.

KEYWORDS:

Genetic association study; HOXB13; Prostate cancer

PMID:
22841674
DOI:
10.1016/j.eururo.2012.07.027
[Indexed for MEDLINE]

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