Homeobox B13 G84E Mutation and Prostate Cancer Risk

Abstract

Background The 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. Objective To obtain precise risk estimates for mutation carriers and information on how these vary by family history and other factors. Design, setting, and participants Two-fold: a systematic review and meta-analysis of published risk estimates, and a kin-cohort study comprising pedigree data on 11 983 PCa patients enrolled during 1993–2014 from 189 UK hospitals and who had been genotyped for HOXB13 G84E. Outcome measurements and statistical analysis Relative 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 limitations A 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. Conclusions PCa 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 summary Men 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 he...

Mutation HOXB13 c.853delT in Martinican prostate cancer patients

“…The screening of the HOXB13 gene is recommended for men who develop an early‐onset and/or familial Pca 11 . Nowadays, the HOXB13 gene is included on the standard laboratory Pca Panel 20 . A recent meta‐analysis of the Pca risk for HOXB13 G84E has shown that the risk of Pca for carriers varies by Pca family and by birth cohort 20 .…”

“…Nowadays, the HOXB13 gene is included on the standard laboratory Pca Panel 20 . A recent meta‐analysis of the Pca risk for HOXB13 G84E has shown that the risk of Pca for carriers varies by Pca family and by birth cohort 20 . Regarding the allele frequency of the HOXB13 c.853delT variant observed in the Pca cohort, it will be necessary to assess relative and absolute Pca risks for HOXB13 c.853delT carriers.…”

Prostate cancer risk variants of the HOXB genetic locus

“…Heterogeneity of measured HOXB13 G84E mutation risk across distinct studies might result as a function of differing carrier proportions of adjacent and untested locus sentinels. This is likely to be correlated with study population characteristics such as family history, age of diagnosis, and pathologic severity 6 , and should be considered with further studies.…”

Identification of Germline Genetic Variants that Increase Prostate Cancer Risk and Influence Development of Aggressive Disease

“…HOXB13 G84E was subsequently confirmed as a moderate penetrance PrCa susceptibility variant in European ancestry populations through a number of independent studies, with consistent evidence demonstrated for strong associations with early-onset and familial PrCa, but importantly no evidence for increased risk of poorer prognosis disease in mutation carriers [ 131 , 132 , 133 , 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. HOXB13 G84E mutations are estimated to be present in up to 5% of European ancestry families with hereditary PrCa [ 140 ], whilst average estimated risks of developing PrCa for heterozygous male carriers are approximately 17% by age 65 rising to 62% by age 85, and further increasing with stronger family history of PrCa [ 141 ]. The HOXB13 G84E mutation is found almost exclusively in European ancestry populations [ 131 , 132 , 133 , 140 , 142 ].…”