HOXB13 Mutation and Prostate Cancer: Studies of Siblings and Agressive Disease.
1Epidemiology & Biostatistics, University of California, San Francisco.Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 02/2013; 22(4). DOI: 10.1158/1055-9965.EPI-12-1154
BACKGROUND: Recent work detected for the first time a high-risk prostate cancer mutation, in homeobox B13 (HOXB13) among European-Americans. METHODS: We further evaluated this G84E missense mutation (rs138213197) in two genetic association studies of prostate cancer: a family-based study of brothers and a case-control study of more aggressive disease (N=2,665 total). We then calculated overall impact of this mutation by pooling all published studies of European-Americans. RESULTS: In our studies the mutation was found exclusively among men with prostate cancer (carrier frequency=1.48%) or unaffected brothers of cases carrying the mutation (frequency=0.34%), and carrying the mutation gave an odds ratio for disease=4.79 (P=0.01). The G84E mutation was more common among men with an earlier age of onset (≤55 years) or a family history of prostate cancer. We also observed for the first time an African-American case carrying the G84E mutation, although at HOXB13 both of his chromosomes were of European-American ancestry. The pooled analysis also indicated that carrying the G84E mutation results in an almost five-fold increase in risk of prostate cancer (P=3.5x10-17), and this risk is even higher among cases with an early age of prostate cancer onset (≤55 years) or a family history of disease: a test of heterogeneity across these strata gives P<1x10-5. CONCLUSIONS: The HOXB13 mutation substantially increases risk of early onset, familial prostate cancer in European-American men. Impact: Testing for the G84E mutation in men with a positive family history may help distinguish those who merit more regular screening for prostate cancer.
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ABSTRACT: The rare but recurrent germline G84E mutation in HOXB13 was recently found to be associated with a significantly increased risk of familial prostate cancer (PCa). However, epidemiologic findings have been inconsistent. In an attempt to confirm and expand the findings that the PCa risk increased in men carrying G84E, we therefore performed a meta-analysis to clarify the association between the germline G84E mutation and PCa risk. We also aim to verify the increased PCa risk with respect to diagnostic age, family history, and disease aggressiveness. Comprehensive search of databases was carried out, and other relevant articles were also identified. Then, the meta-analyses were conducted according to the standard guidelines. A total of 11 studies with 120,167 participants were included on the basis of inclusion criteria. The G84E allele carrier frequencies ranged from 0.1 to 4.9 % in the patients with PCa, as compared with 0 to 1.4 % in control subjects. Men with the HOXB13 G84E variant had a 4.51-fold higher relative risk of PCa compared with non-carriers (95 % CI 3.28-6.20). The much higher risks were observed in individuals with early onset (odds ratio (OR) = 9.73, 95 % confidence interval (CI) 6.57-14.39), more than two affected relatives (OR = 7.27, 95 % CI 4.02-13.15), and highly aggressive disease (OR = 5.81, 95 % CI 3.72-9.08). Our findings provide further evidences that the rare mutation in HOXB13 contributes to both hereditary and sporadic PCa risk. Despite the low G84E carrier rate, biological and clinical implications of the mutation in subjects with early onset, more than two affected relatives, and highly aggressive disease remain important in continued investigation.
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ABSTRACT: To determine the prevalence and clinical correlates of the G84E mutation in the homeobox transcription factor (or HOXB13) gene using DNA samples from 9,559 men with prostate cancer undergoing radical prostatectomy. DNA samples from men treated with radical prostatectomy at the University of Michigan and John Hopkins University were genotyped for G84E and confirmed by Sanger sequencing. The frequency and distribution of this allele was determined according to specific patient characteristics (family history, age at diagnosis, pathologic Gleason grade and stage). 128 of 9,559 patients were heterozygous carriers of G84E (1.3%). Patients who possessed the variant were more likely to have a family history of prostate cancer (46.0% vs. 35.4% p=0.006). G84E carriers were also more likely diagnosed at a younger age compared to non-carriers (55.2 years vs. 58.1 years; p<0.0001). No difference in the proportion of patients diagnosed with high-grade or advanced stage tumors by carrier status was observed. In our study, carriers of the rare G84E variant in HOXB13 were both younger at the time of diagnosis and more likely to have a family history of prostate cancer compared to homozygotes for the wild-type allele. No significant differences in allele frequency were detected according to select clinical characteristics of prostate cancer. Further investigation is required to evaluate the role of HOXB13 in prostate carcinogenesis.
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ABSTRACT: HOXB13 (G84E) was reported to significantly increase risk for prostate cancer. The goal of the current analysis was to assess the prevalence of G84E in ethnically-diverse high-risk men undergoing prostate cancer screening and place the carrier frequency within the context of prevalence estimates from reported studies to gain insight into the future role of this mutation in genetic counseling. PRAP is a prostate cancer screening program for unaffected men ages 35-69 with a family history of prostate cancer or African descent. HOXB13 G84E was genotyped by pyrosequencing in 649 PRAP participants with available DNA. Prevalence of the mutation was calculated for PRAP and for reported studies and exact binomial confidence intervals were generated. Prevalence of the G84E mutation in non-African PRAP men was 0.73 %. When placed in context of the literature, this was higher than reported controls. One G84E mutation carrier was notably of Hispanic background. While the HOXB13 G84E mutation may be rare, there may be a future role in genetic testing for this mutation after further studies of clinical utility in assessing prostate cancer risk.