HOXB13 Mutation and Prostate Cancer: Studies of Siblings and Agressive Disease.
ABSTRACT 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.
- SourceAvailable from: Brennan Decker[Show abstract] [Hide abstract]
ABSTRACT: Prostate cancer (PC) is the most common noncutaneous cancer in men, and epidemiological studies suggest that about 40% of PC risk is heritable. Linkage analyses in hereditary PC families have identified multiple putative loci. However, until recently, identification of specific risk alleles has proven elusive. Cooney et al used linkage mapping and segregation analysis to identify a putative risk locus on chromosome 17q21-22. In search of causative variant(s) in genes from the candidate region, a novel, potentially deleterious G84E substitution in homeobox transcription factor gene HOXB13 was observed in multiple hereditary PC families. In follow-up testing, the G84E allele was enriched in cases, especially those with an early diagnosis or positive family history of disease. This finding was replicated by others, confirming HOXB13 as a PC risk gene. The HOXB13 protein plays diverse biological roles in embryonic development and terminally differentiated tissue. In tumor cell lines, HOXB13 participates in a number of biological functions, including coactivation and localization of the androgen receptor and FOXA1. However, no consensus role has emerged and many questions remain. All HOXB13 variants with a proposed role in PC risk are predicted to damage the protein and lie in domains that are highly conserved across species. The G84E variant has the strongest epidemiological support and lies in a highly conserved MEIS protein-binding domain, which binds cofactors required for activation. On the basis of epidemiological and biological data, the G84E variant likely modulates the interaction between the HOXB13 protein and the androgen receptor, as well as affecting FOXA1-mediated transcriptional programming. However, further studies of the mutated protein are required to clarify the mechanisms by which this translates into PC risk.Pharmacogenomics and Personalized Medicine 01/2014; 7:193-201.
- [Show abstract] [Hide abstract]
ABSTRACT: The HOXB13 gene has been implicated in prostate cancer (PrCa) susceptibility. We performed a high resolution fine-mapping analysis to comprehensively evaluate the association between common genetic variation across the HOXB genetic locus at 17q21 and PrCa risk. This involved genotyping 700 SNPs using a custom Illumina iSelect array (iCOGS) followed by imputation of 3195 SNPs in 20,440 PrCa cases and 21,469 controls in The PRACTICAL consortium. We identified a cluster of highly correlated common variants situated within or closely upstream of HOXB13 that were significantly associated with PrCa risk, described by rs117576373 (OR 1.30, P = 2.62×10(-14)). Additional genotyping, conditional regression and haplotype analyses indicated that the newly identified common variants tag a rare, partially correlated coding variant in the HOXB13 gene (G84E, rs138213197), which has been identified recently as a moderate penetrance PrCa susceptibility allele. The potential for GWAS associations detected through common SNPs to be driven by rare causal variants with higher relative risks has long been proposed; however, to our knowledge this is the first experimental evidence for this phenomenon of synthetic association contributing to cancer susceptibility.PLoS Genetics 02/2014; 10(2):e1004129. · 8.17 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Prostate cancer is considered a disease of older men (aged >65 years), but today over 10% of new diagnoses in the USA occur in young men aged ≤55 years. Early-onset prostate cancer, that is prostate cancer diagnosed at age ≤55 years, differs from prostate cancer diagnosed at an older age in several ways. Firstly, among men with high-grade and advanced-stage prostate cancer, those diagnosed at a young age have a higher cause-specific mortality than men diagnosed at an older age, except those over age 80 years. This finding suggests that important biological differences exist between early-onset prostate cancer and late-onset disease. Secondly, early-onset prostate cancer has a strong genetic component, which indicates that young men with prostate cancer could benefit from evaluation of genetic risk. Furthermore, although the majority of men with early-onset prostate cancer are diagnosed with low-risk disease, the extended life expectancy of these patients exposes them to long-term effects of treatment-related morbidities and to long-term risk of disease progression leading to death from prostate cancer. For these reasons, patients with early-onset prostate cancer pose unique challenges, as well as opportunities, for both research and clinical communities. Current data suggest that early-onset prostate cancer is a distinct phenotype-from both an aetiological and clinical perspective-that deserves further attention.Nature Reviews Urology 05/2014; · 4.79 Impact Factor