Confirmation of the HOXB13 G84E Germline Mutation in Familial Prostate Cancer

Abstract

Background A recent study of familial and early onset prostate cancer reported a recurrent rare germline mutation of HOXB13 among men of European descent. The gene resides within the 17q21 hereditary prostate cancer linkage interval. Methods We evaluated the G84E germline mutation (rs138213197) of HOXB13 in a case-control study of familial prostate cancer at Vanderbilt University to independently evaluate the association of the mutation with familial prostate cancer. We genotyped 928 familial prostate cancer probands, and 930 control probands without a personal or family history of prostate cancer. Results Our study confirmed the association between the G84E mutation of HOXB13 and risk of prostate cancer among subjects of European descent. We observed the mutation in 16 familial cases and in two controls, each as heterozygotes. The odds ratio for prostate cancer was 7.9 (95% CI 1.8 – 34.5, P = 0.0062) among carriers of the mutation. The carrier rate was 1.9% among all familial case probands, and 2.7% among probands of pedigrees with ≥ 3 affected. In a separate case series of 268 probands of European descent with no additional family history of prostate cancer, the carrier rate was 1.5%. Conclusions The germline mutation G84E of HOXB13 is a rare but recurrent mutation associated with elevated risk of prostate cancer in men of European descent, with an effect size that is greater than observed for previously validated risk variants of genome wide association studies. Impact This study independently confirms the association of a germline HOXB13 mutation with familial prostate cancer.

The role of germline mutations in the BRCA1/2 and mismatch repair genes in men ascertained for early-onset and/or familial prostate cancer

“…Recently, a variant in the HOXB13 gene was identified as the first germline mutation consistently and specifically associated with familial PrCa in men of European ancestry [1]. The increased PrCa risk conferred by the p.(Gly84Glu) mutation, also described as G84E, has been confirmed by several other authors [2][3][4][5][6] and it is now believed that this variant is a founder mutation originated in Scandinavia [4][5][6]. Subsequent studies have identified other HOXB13 variants in PrCa patients of African and Asian descent [1,2,7] and we have recently performed the first systematic full gene analysis of HOXB13 in early-onset and/or familial PrCa patients of Southern European origin [8].…”

Prostate cancer in young men: an important clinical entity

“…The variant was subsequently shown to be associated with both hereditary and sporadic prostate cancer in many independent study populations. 63–70 Continued focus on early onset prostate cancer cases may provide an opportunity to identify novel genetic loci associated with increased risk for this disease.…”

Dysregulation of the homeobox transcription factor gene HOXB13: role in prostate cancer

“…These investigators genotyped 930 controls without a personal or family history of PC and 928 familial cases, and observed the mutation in 16 of the familial cases versus only two controls (OR =7.9, 95% CI =1.8–34.5). The carrier rate was 1.9% in all probands, but it went up 30% in cases who had ≥3 affected family members 45. The primary result was also confirmed in the much larger International Consortium for Prostate Cancer Genetics study in which investigators genotyped the G84E variant and 14 other single-nucleotide polymorphisms (SNPs) in 2,443 families 46.…”