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Confirmation of the HOXB13 G84E germline mutation in familial prostate cancer.

ABSTRACT: 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.We evaluated the G84E germline mutation (rs138213197) of HOXB13 in a case-control study of familial prostate cancer at Vanderbilt University (Nashville, TN) 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.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 (OR) for prostate cancer was 7.9 [95% confidence interval, (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%.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.This study independently confirms the association of a germline HOXB13 mutation with familial prostate cancer.

SUBMITTER: Breyer JP

PROVIDER: S-EPMC3415588 | biostudies-literature | 2012 Aug

REPOSITORIES: biostudies-literature

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Confirmation of the HOXB13 G84E germline mutation in familial prostate cancer.

Breyer Joan P JP Avritt T Grant TG McReynolds Kate M KM Dupont William D WD Smith Jeffrey R JR

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 20120619 8

<h4>Background</h4>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.<h4>Methods</h4>We evaluated the G84E germline mutation (rs138213197) of HOXB13 in a case-control study of familial prostate cancer at Vanderbilt University (Nashville, TN) to independently evaluate the association of the mutation with familial prostate cance ...[more]

PMID: 22714738

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Project description:BackgroundThe homeobox B13 (HOXB13) G84E mutation has been recommended for use in genetic counselling for prostate cancer (PCa), but the magnitude of PCa risk conferred by this mutation is uncertain.ObjectiveTo obtain precise risk estimates for mutation carriers and information on how these vary by family history and other factors.Design, setting, and participantsTwo-fold: a systematic review and meta-analysis of published risk estimates, and a kin-cohort study comprising pedigree data on 11983 PCa patients enrolled during 1993-2014 from 189 UK hospitals and who had been genotyped for HOXB13 G84E.Outcome measurements and statistical analysisRelative and absolute PCa risks. Complex segregation analysis with ascertainment adjustment to derive age-specific risks applicable to the population, and to investigate how these vary by family history and birth cohort.Results and limitationsA meta-analysis of case-control studies revealed significant heterogeneity between reported relative risks (RRs; range: 0.95-33.0, p<0.001) and differences by case selection (p=0.007). Based on case-control studies unselected for PCa family history, the pooled RR estimate was 3.43 (95% confidence interval [CI] 2.78-4.23). In the kin-cohort study, PCa risk for mutation carriers varied by family history (p<0.001). There was a suggestion that RRs decrease with age, but this was not significant (p=0.068). We found higher RR estimates for men from more recent birth cohorts (p=0.004): 3.09 (95% CI 2.03-4.71) for men born in 1929 or earlier and 5.96 (95% CI 4.01-8.88) for men born in 1930 or later. The absolute PCa risk by age 85 for a male HOXB13 G84E carrier varied from 60% for those with no PCa family history to 98% for those with two relatives diagnosed at young ages, compared with an average risk of 15% for noncarriers. Limitations include the reliance on self-reported cancer family history.ConclusionsPCa risks for HOXB13 G84E mutation carriers are heterogeneous. Counselling should not be based on average risk estimates but on age-specific absolute risk estimates tailored to individual mutation carriers' family history and birth cohort.Patient summaryMen who carry a hereditary mutation in the homeobox B13 (HOXB13) gene have a higher than average risk for developing prostate cancer. In our study, we examined a large number of families of men with prostate cancer recruited across UK hospitals, to assess what other factors may contribute to this risk and to assess whether we could create a precise model to help in predicting a man's prostate cancer risk. We found that the risk of developing prostate cancer in men who carry this genetic mutation is also affected by a family history of prostate cancer and their year of birth. This information can be used to assess more personalised prostate cancer risks to men who carry HOXB13 mutations and hence better counsel them on more personalised risk management options, such as tailoring prostate cancer screening frequency.

Dataset Information

Confirmation of the HOXB13 G84E germline mutation in familial prostate cancer.

Publications

Confirmation of the HOXB13 G84E germline mutation in familial prostate cancer.

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