A novel Germline mutation in HOXB13 is associated with prostate cancer risk in Chinese men

Abstract

BACKGROUND A rare mutation G84E in HOXB13 was recently identified to be associated with prostate cancer (PCa) in Caucasians. The goal of this study is to test association between HOXB13 genetic variants and PCa risk in Chinese men. METHODS All study subjects were part of the Chinese Consortium for Prostate Cancer Genetics (China PCa). In the first stage, we screened for mutations by sequencing the HOXB13 coding region in 96 unrelated PCa patients. In stage 2, G84E and novel mutations found in stage 1 were genotyped in 671 PCa patients and 1,536 controls. In stage 3, mutation status in 751 additional PCa patients was imputed via haplotype. RESULTS The G84E mutation was not detected in this study. However, a novel mutation, G135E, was identified among 96 patients in stage 1. It was also observed twice in 575 additional PCa patients but not in 1,536 control subjects of stage 2. The frequency of G135E was significantly different between cases and controls, with a P-value of 0.027, based on Fisher’s exact test. Haplotype estimation showed that G135E mutation carriers shared a unique haplotype that was not observed in other subjects. In stage 3, two more PCa patients were predicted to carry the G135E mutation. CONCLUSIONS We identified a novel rare mutation in the HOXB13 gene, G135E, which appears to be a founder mutation. This mutation is associated with increased PCa risk in Chinese men. Consistent with a previous report, our findings provide further evidence that rare mutations in HOXB13 contribute to PCa risk. Prostate 73: 169–175, 2013.

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

“…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]. These works have demonstrated that HOXB13 contributes to inherited PrCa predisposition, but also that allelic heterogeneity exists depending on the patients' geographical or ethnic background.…”

Oncogenic mechanisms of HOXB13 missense mutations in prostate carcinogenesis

“…With the recent description of HOXB13 germline mutations predisposing to prostate cancer development [4,16,17], the relevance of HOXB13 for prostate carcinogenesis gained a new perspective. Although found in only up to 5% of the prostate cancer cases of European descent showing familial clustering, the G84E mutation was the first genetic variant independently validated to be associated with site-specific hereditary prostate cancer predisposition [4–6,12,13].…”

“…Although this variant only accounts for a small fraction of the prostate cancer cases, it confers an increased relative risk of 4.51-fold and is overrepresented in early-onset and familial prostate cancer [4,14,15]. Other HOXB13 variants have also been found in different ethnic groups, suggesting allelic heterogeneity in different populations [4,16,17]. …”

Translating Genetic Risk Factors for Prostate Cancer to the Clinic: 2013 and Beyond

“…It was more common in Nordic countries and less common in North America and Australia. And within HOXB13 carrier families the G84E mutation was more common in men with a diagnosis of PrCa [70]. A meta-analysis of 24 trials with 97,844 participants by Shang et al identified that the frequency of the G84E mutation was higher among cases with younger age at onset with an OR of 10.1 (95% CI: 5.97-17.12) and among patients with family history with an OR of 5.01 [71].…”