Familial prostate cancer and HOXB13 founder mutations: geographic and racial/ethnic variations

Genome-wide association studies (GWAS) have recently made major contributions to the identification of mutations inclusive of G84E in HOXB13 for prostate cancer (Ewing et al. 2012) as featured in this editorial regarding the paper by Xu et al. (2012) published in this issue of the journal. However, along with the contributions of GWAS, there has been the rapid emergence of new technologies dealing with next-generation DNA sequencing (NGS) technology, which are providing unique opportunities to advance this knowledge. Specifically by sequencing the entire genome, entire exome or entire transcriptome, NGS allows an unbiased view to detect genetic defects in familial cancer aggregations as demonstrated by recent cancer genetic/ genomic studies (Thompson et al. 2012; Hellebrand et al. 2011). The exome sequencing method, first developed in 2009, uses the next-generation sequencers to sequence only the exome, that is, the coding part, of the targeted genome (Gnirke et al. 2009; Ng et al. 2009; Maher 2009; Choi et al. 2009). When compared to whole genome sequencing, the advantages of exome sequencing include its lower cost and simpler analysis of the sequences, while the mutations identified will provide functional information by focusing on the mutated gene. More importantly, as mutations in the coding region make up 85 % of the genetic disease-causing mutations (Cooper et al. 1995), identifying coding mutations should provide an opportunity with a high chance of determining the mutations contributing to a particular genetic disease. The major technical challenge of exome sequencing was the standardization of the exome DNA extraction process to ensure inclusion of exon DNA templates for NGS sequencing. This problem has been solved with the development of commercial exome extraction kits by NimbleGen, Agilent, and Illumina companies in 2010–2011. Exome sequencing has become a matured method for genetic study, and provides a powerful means to detect genetic alterations affecting known genes in cancers (Gnirke et al. 2009; Ng et al. 2009; Maher 2009; Choi et al. 2009). This background is being discussed in this editorial with respect to the Xu et al. (2012) paper, given the potential that exome sequencing advances have for scientifically enhancing GWAS. A recurrent, albeit rare, mutation (G84E) in HOXB13 was recently identified by Ewing et al. (2012) in a previously recognized region of linkage at 17q21-22 as harboring an increased risk for familial prostate cancer. Once confirmed and further clarified, this observation will have the potential to be clinically translatable. Xu et al. (2012) have utilized a large international sample of prostate cancer-prone families who were recruited by the International Consortium for Prostate Cancer Genetics (ICPCG) in order to confirm the findings of Ewing et al. (2012) that the G84E mutation is rare, but that it is significantly associated with predisposition to prostate cancer. In the Xu et al. cohort, at least one mutation carrier was identified in each of 112 prostate cancer families (4.6 % of all 2,443 prostate cancer families studied), all of whom were of European descent. The G84E mutation was more frequently encountered in males Invited editorial on Xu et al. (2012).