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

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

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

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.

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.

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).

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.