HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG)

Abstract

Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10−8 [odds ratio 4.42 (95 % confidence interval 2.56–7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10−6). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-012-1229-4) contains supplementary material, which is available to authorized users.

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

“…Several studies have identified a specific HOXB13 mutation in 1.4-4.6% of individuals (primarily of Northern European ancestry) meeting these criteria. [53][54][55] Identifying the basis of familial prostate cancer is ongoing, and genes found to date account for a small portion of families. However, referral may be appropriate for these families to help address concerns and provide screening recommendations.…”

HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk

“…Only an index case was originally genotyped, and additional individuals were studied only to confirm segregation of the mutation. Seventy-six index individuals overlapped with those genotyped in the large multinational ICPCG study (19). To investigate the cosegregation of the G84E mutation in nonoverlapping, mutation-positive families, additional healthy and affected family members were genotyped.…”

“…Fifteen of these 32 families overlapped with the ICPCG dataset (19). Cosegregation of G84E with prostate cancer in the remaining 17 families was assessed by genotyping an additional 28 healthy and 37 affected family members, for whom DNA samples were available.…”

“…Given the linkage evidence to the 17q21-22 locus in Finnish prostate cancer families (10), and the exceptionally high proportion of Finnish families with the G84E mutation, as shown in a recent International Consortium for Prostate Cancer Genetics (ICPCG) study (19), we genotyped the G84E mutation in 4,571 prostate cancer cases and 5,467 controls, together with 516 benign prostate hyperplasia samples, 10 prostatic cell lines, and 19 LuCaP xenografts. We also investigated its role in prostate cancer risk, clinical outcome, and survival.…”

The 2013 Genetics Society of America Medal

“…While the biomedical relevance of this work is extremely high (17% of American men will get prostate cancer), the genetics are proving to be somewhat more difficult than trait mapping in dogs. However, recent studies have successfully identified candidate loci associated with susceptibility to prostate cancer in high-risk families and certain populations (Jin et al 2012;Stott-Miller et al 2012;Taioli et al 2012;Xu et al 2013).…”