HOXB13 mutations in a population-based, case-control study of prostate cancer.
ABSTRACT: BACKGROUND:Prostate cancer (PC) is the most frequently diagnosed non-skin malignancy in men in the Western world, yet few disease-associated mutations have been found. Recently, a low frequency recurring mutation in the HOXB13 gene was reported among both hereditary PC families and men from the general population. MATERIALS AND METHODS:We determined the distribution and frequency of the G84E HOXB13 variant in 1,310 incipient PC cases and 1,259 age-mated controls from a population-based, case-control study of PC. RESULTS:The G84E mutation was more frequent in cases than controls (1.3% vs. 0.4%, respectively), and men with the HOXB13 G84E variant had a 3.3-fold higher relative risk of PC compared with noncarriers (95% CI, 1.21-8.96). There was a stronger association between the G84E variant and PC among men with no first-degree relative with PC (OR, 4.04; 95% CI, 1.12-14.51) compared to men with a family history of PC (OR, 1.49; 95% CI, 0.30-7.50; P?=?0.36 for interaction). We observed some evidence of higher risk estimates associated with the variant for men with higher versus lower Gleason score (OR, 4.13; 95% CI, 1.38-12.38 vs. OR, 2.71; 95% CI, 0.88-8.30), and advanced versus local stage (OR, 4.47; 95% CI, 1.28-15.57 vs. OR, 2.98; 95% CI, 1.04-8.49), however these differences were not statistically different. CONCLUSIONS:These results confirm the association of a rare HOXB13 mutation with PC in the general population and suggest that this variant may be associated with features of more aggressive disease.
Project description:The G84E variant of HOXB13 was recently found to be associated with a significantly increased risk of prostate cancer in a case control study. We estimated the prevalence of this mutation in a clinical population of men at risk for prostate cancer who were scheduled to undergo prostate biopsy.We prospectively collected clinical information and DNA samples from men who underwent diagnostic prostate biopsy between June 2005 and October 2011. We genotyped samples for HOXB13 G84E using the MassARRAY® system. We determined the prevalence of the G84E variant in the overall cohort, among patients with a positive family history and among men age 55 years or younger.A total of 1,175 subjects underwent biopsy, of whom 948 had a DNA sample for analysis. The G84E variant was detected in 4 patients (prevalence 0.42%, 95% CI 0.12-1.08), of whom 3 had prostate cancer on biopsy. None of 301 patients with a positive family history (prevalence 0.00%, 95% CI 0.00-1.22) and 1 of 226 patients age 55 years or younger tested positive (prevalence 0.44%, 95% CI 0.01-2.44).The HOXB13 G84E variant is rare in this cohort, even among those with a positive family history. Our findings question the utility of testing for this variant among unselected men presenting for a diagnostic prostate biopsy.
Project description: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.
Project description:A rare nonconservative substitution (G84E) in the HOXB13 gene has been shown to be associated with risk of prostate cancer. DNA samples from male patients included in the Mayo Clinic Biobank (MCB) were genotyped to determine the frequency of the G84E mutation and its association with various cancers.Subjects were genotyped using a custom TaqMan (Applied Biosystems) assay for G84E (rs138213197). In addition to donating a blood specimen, all MCB participants completed a baseline questionnaire to collect information on medical history and family history of cancer.Forty-nine of 9,012 male patients were carriers of G84E (0.5%). Thirty-one percent (n = 2,595) of participants had been diagnosed with cancer, including 51.1% of G84E carriers compared with just 30.6% of noncarriers (P = 0.004). G84E was most frequently observed among men with prostate cancer compared with men without cancer (P < 0.0001). However, the mutation was also more commonly observed in men with bladder cancer (P = 0.06) and leukemia (P = 0.01). G84E carriers were more likely to have a positive family history of prostate cancer in a first-degree relative compared to noncarriers (36.2% vs. 16.0%, P = 0.0003).Our study confirms the association between the HOXB13 G84E variant and prostate cancer and suggests a novel association between G84E and leukemia and a suggestive association with bladder cancer. Future investigation is warranted to confirm these associations in order to improve our understanding of the role of germline HOXB13 mutations in human cancer.The associations between HOXB13 and prostate, leukemia, and bladder suggest that this gene is important in carcinogenesis.
Project description:Germline HOXB13 G84E mutation (rs138213197) has been described associated with prostate cancer (PCa) susceptibility but results of different studies are inconsistent. We conducted this meta-analysis to evaluate the specific role of this mutation. Relevant available studies were identified by searching the databases Pubmed, Embase and Web of Science. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to measure the strength of the association. Subgroup analysis were performed to evaluate the specific role of rs138213197 in disease aggressiveness, diagnostic age and family history. Furthermore, trial sequential analysis (TSA) was conducted for the first time to estimate whether the evidence of the results is sufficient. Our results indicated that significant increased PCa susceptibility was associated with rs138213197 compared with non-carriers (OR = 3.38, 95% CI: 2.45-4.66). Besides, in subgroup analysis, HOXB13 G84E variant was obviously associated with early onset (OR = 2.90, 95% CI: 2.24-3.75), affected relatives (OR = 2.60, 95% CI 2.19-3.10) and highly aggressive disease (OR = 2.38, 95% CI 1.84-3.08). By TSA, the findings in the current study were based on sufficient evidence. Therefore, our results indicated that the G84E mutation in HOXB13 gene might increase susceptibility to PCa.
Project description:<h4>Objective</h4>To determine the prevalence and clinical correlates of the G84E mutation in the homeobox transcription factor, or HOXB13, gene using DNA samples from 9559 men with prostate cancer undergoing radical prostatectomy.<h4>Patients and methods</h4>DNA samples from men treated with radical prostatectomy at the University of Michigan and John Hopkins University were genotyped for G84E and this was confirmed by Sanger sequencing. The frequency and distribution of this allele was determined according to specific patient characteristics (family history, age at diagnosis, pathological Gleason grade and stage).<h4>Results</h4>Of 9559 patients, 128 (1.3%) were heterozygous carriers of G84E. Patients who possessed the variant were more likely to have a family history of prostate cancer than those who did not (46.0 vs 35.4%; P = 0.006). G84E carriers were also more likely to be diagnosed at a younger age than non-carriers (55.2 years vs 58.1 years; P < 0.001). No difference in the proportion of patients diagnosed with high grade or advanced stage tumours according to carrier status was observed.<h4>Conclusions</h4>In the present 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 with homozygotes for the wild-type allele. No significant differences in allele frequency were detected according to selected clinical characteristics of prostate cancer. Further investigation is required to evaluate the role of HOXB13 in prostate carcinogenesis.
Project description: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.
Project description: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 11983 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 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.
Project description:Prostate cancer has a strong familial component but uncovering the molecular basis for inherited susceptibility for this disease has been challenging. Recently, a rare, recurrent mutation (G84E) in HOXB13 was reported to be associated with prostate cancer risk. Confirmation and characterization of this finding is necessary to potentially translate this information to the clinic. To examine this finding in a large international sample of prostate cancer families, we genotyped this mutation and 14 other SNPs in or flanking HOXB13 in 2,443 prostate cancer families recruited by the International Consortium for Prostate Cancer Genetics (ICPCG). At least one mutation carrier was found in 112 prostate cancer families (4.6 %), all of European descent. Within carrier families, the G84E mutation was more common in men with a diagnosis of prostate cancer (194 of 382, 51 %) than those without (42 of 137, 30 %), P = 9.9 × 10(-8) [odds ratio 4.42 (95 % confidence interval 2.56-7.64)]. A family-based association test found G84E to be significantly over-transmitted from parents to affected offspring (P = 6.5 × 10(-6)). Analysis of markers flanking the G84E mutation indicates that it resides in the same haplotype in 95 % of carriers, consistent with a founder effect. Clinical characteristics of cancers in mutation carriers included features of high-risk disease. These findings demonstrate that the HOXB13 G84E mutation is present in ~5 % of prostate cancer families, predominantly of European descent, and confirm its association with prostate cancer risk. While future studies are needed to more fully define the clinical utility of this observation, this allele and others like it could form the basis for early, targeted screening of men at elevated risk for this common, clinically heterogeneous cancer.
Project description:An efficient approach to characterizing the disease burden of rare genetic variants is to impute them into large well-phenotyped cohorts with existing genome-wide genotype data using large sequenced referenced panels. The success of this approach hinges on the accuracy of rare variant imputation, which remains controversial. For example, a recent study suggested that one cannot adequately impute the HOXB13 G84E mutation associated with prostate cancer risk (carrier frequency of 0.0034 in European ancestry participants in the 1000 Genomes Project). We show that by utilizing the 1000 Genomes Project data plus an enriched reference panel of mutation carriers we were able to accurately impute the G84E mutation into a large cohort of 83,285 non-Hispanic White participants from the Kaiser Permanente Research Program on Genes, Environment and Health Genetic Epidemiology Research on Adult Health and Aging cohort. Imputation authenticity was confirmed via a novel classification and regression tree method, and then empirically validated analyzing a subset of these subjects plus an additional 1,789 men from Kaiser specifically genotyped for the G84E mutation (r2 = 0.57, 95% CI = 0.37–0.77). We then show the value of this approach by using the imputed data to investigate the impact of the G84E mutation on age-specific prostate cancer risk and on risk of fourteen other cancers in the cohort. The age-specific risk of prostate cancer among G84E mutation carriers was higher than among non-carriers. Risk estimates from Kaplan-Meier curves were 36.7% versus 13.6% by age 72, and 64.2% versus 24.2% by age 80, for G84E mutation carriers and non-carriers, respectively (p = 3.4x10-12). The G84E mutation was also associated with an increase in risk for the fourteen other most common cancers considered collectively (p = 5.8x10-4) and more so in cases diagnosed with multiple cancer types, both those including and not including prostate cancer, strongly suggesting pleiotropic effects. [corrected].
Project description:The HOXB13 germline variant G84E (rs138213197) was recently described in men of European descent, with the highest prevalence in Northern Europe. The G84E mutation has not been found in patients of African or Asian ancestry, which may carry other HOXB13 variants, indicating allelic heterogeneity depending on the population. In order to gain insight into the full scope of coding HOXB13 mutations in Portuguese prostate cancer patients, we decided to sequence the entire coding region of the HOXB13 gene in 462 early-onset or familial/hereditary cases. Additionally, we searched for somatic HOXB13 mutations in 178 prostate carcinomas to evaluate their prevalence in prostate carcinogenesis. Three different patients were found to carry in their germline DNA two novel missense variants, which were not identified in 132 control subjects. Both variants are predicted to be deleterious by different in silico tools. No somatic mutations were found. These findings further support the hypothesis that different rare HOXB13 mutations may be found in different ethnic groups. Detection of mutations predisposing to prostate cancer may require re-sequencing rather than genotyping, as appropriate to the population under investigation.