Introduction
By sequencing coding regions of more than 200 genes in a previously identified region of linkage at 17q21–22 (Lange et al. 2003; Gillanders et al. 2004; Xu et al. 2005; Lange et al. 2007; Cropp et al. 2011) a rare but recurrent mutation (G84E) in HOXB13 was recently identified in four of 94 probands from prostate cancer families. (Ewing et al. 2012) The mutation co-segregated with prostate cancer in these four families and was found to be significantly more common among 5,083 unrelated prostate cancer patients (1.4 %) than control subjects (0.1 %) of European descent (p = 8.5 × 10−7) leading to odds ratio (OR) estimates of tenfold or more. In this initial report, the frequency of the mutation was higher in prostate cancer patients with early-onset disease (age at diagnosis ≤55 years old, 2.2 %) or with a positive family history (2.2 %), and most common in patients with both of these features (3.1 %). If confirmed, these findings provide support for the concept that rare, moderately penetrant mutations as well as common, low-penetrance prostate cancer risk-associated variants identified from genome-wide association studies (GWAS) (Gudmundsson et al. 2007a, b, 2008, 2009; Yeager et al. 2007, 2009; Thomas et al. 2008; Eeles et al. 2008, 2009; Sun et al. 2008; Xu et al. 2010; Kote-Jarai et al. 2011a; Takata et al. 2010; Akamatsu et al. 2012; Haiman et al. 2011) both contribute to prostate cancer risk. The identification and characterization of genetic variants reproducibly associated with substantial increases in prostate cancer risk would provide enhanced ability to identify men most likely to benefit from early disease screening.
Prostate cancer demonstrates wide differences in incidence and mortality across populations within the United States and throughout the world. In an attempt to confirm and expand the observations of Ewing et al. (2012), we examined the frequency of HOXB13 G84E mutations in prostate cancer families across different ancestries and geographic regions. We genotyped this mutation and other known variants in HOXB13 in 2,443 hereditary prostate cancer families recruited by members of the International Consortium for Prostate Cancer Genetics (ICPCG), a large NCI-funded collaborative resource for studies of genetic susceptibility for hereditary prostate cancer.