Identification of Genes with Rare Loss of Function Variants Associated with Aggressive Prostate Cancer and Survival.

BACKGROUND: Prostate cancer (PrCa) is a substantial cause of mortality among men globally. Rare germline mutations in BRCA2 have been validated robustly as increasing risk of aggressive forms with a poorer prognosis; however, evidence remains less definitive for other genes. OBJECTIVE: To detect genes associated with PrCa aggressiveness, through a pooled analysis of rare variant sequencing data from six previously reported studies in the UK Genetic Prostate Cancer Study (UKGPCS). DESIGN, SETTING, AND PARTICIPANTS: We accumulated a cohort of 6805 PrCa cases, in which a set of ten candidate genes had been sequenced in all samples. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We examined the association between rare putative loss of function (pLOF) variants in each gene and aggressive classification (defined as any of death from PrCa, metastatic disease, stage T4, or both stage T3 and Gleason score ≥8). Secondary analyses examined staging phenotypes individually. Cox proportional hazards modelling and Kaplan-Meier survival analyses were used to further examine the relationship between mutation status and survival. RESULTS AND LIMITATIONS: We observed associations between PrCa aggressiveness and pLOF mutations in ATM, BRCA2, MSH2, and NBN (odds ratio = 2.67-18.9). These four genes and MLH1 were additionally associated with one or more secondary analysis phenotype. Carriers of germline mutations in these genes experienced shorter PrCa-specific survival (hazard ratio = 2.15, 95% confidence interval 1.79-2.59, p = 4 × 10-16) than noncarriers. CONCLUSIONS: This study provides further support that rare pLOF variants in specific genes are likely to increase aggressive PrCa risk and may help define the panel of informative genes for screening and treatment considerations. PATIENT SUMMARY: By combining data from several previous studies, we have been able to enhance knowledge regarding genes in which inherited mutations would be expected to increase the risk of more aggressive PrCa. This may, in the future, aid in the identification of men at an elevated risk of dying from PrCa.

Characterizing prostate cancer risk through multi-ancestry genome-wide discovery of 187 novel risk variants.

The transferability and clinical value of genetic risk scores (GRSs) across populations remain limited due to an imbalance in genetic studies across ancestrally diverse populations. Here we conducted a multi-ancestry genome-wide association study of 156,319 prostate cancer cases and 788,443 controls of European, African, Asian and Hispanic men, reflecting a 57% increase in the number of non-European cases over previous prostate cancer genome-wide association studies. We identified 187 novel risk variants for prostate cancer, increasing the total number of risk variants to 451. An externally replicated multi-ancestry GRS was associated with risk that ranged from 1.8 (per standard deviation) in African ancestry men to 2.2 in European ancestry men. The GRS was associated with a greater risk of aggressive versus non-aggressive disease in men of African ancestry (P = 0.03). Our study presents novel prostate cancer susceptibility loci and a GRS with effective risk stratification across ancestry groups.

Germline Sequencing Analysis to Inform Clinical Gene Panel Testing for Aggressive Prostate Cancer.

Importance: Germline gene panel testing is recommended for men with advanced prostate cancer (PCa) or a family history of cancer. While evidence is limited for some genes currently included in panel testing, gene panels are also likely to be incomplete and missing genes that influence PCa risk and aggressive disease. Objective: To identify genes associated with aggressive PCa. Design, Setting, and Participants: A 2-stage exome sequencing case-only genetic association study was conducted including men of European ancestry from 18 international studies. Data analysis was performed from January 2021 to March 2023. Participants were 9185 men with aggressive PCa (including 6033 who died of PCa and 2397 with confirmed metastasis) and 8361 men with nonaggressive PCa. Exposure: Sequencing data were evaluated exome-wide and in a focused investigation of 29 DNA repair pathway and cancer susceptibility genes, many of which are included on gene panels. Main Outcomes and Measures: The primary study outcomes were aggressive (category T4 or both T3 and Gleason score ≥8 tumors, metastatic PCa, or PCa death) vs nonaggressive PCa (category T1 or T2 and Gleason score ≤6 tumors without known recurrence), and metastatic vs nonaggressive PCa. Results: A total of 17 546 men of European ancestry were included in the analyses; mean (SD) age at diagnosis was 65.1 (9.2) years in patients with aggressive PCa and 63.7 (8.0) years in those with nonaggressive disease. The strongest evidence of association with aggressive or metastatic PCa was noted for rare deleterious variants in known PCa risk genes BRCA2 and ATM (P ≤ 1.9 × 10-6), followed by NBN (P = 1.7 × 10-4). This study found nominal evidence (P < .05) of association with rare deleterious variants in MSH2, XRCC2, and MRE11A. Five other genes had evidence of greater risk (OR≥2) but carrier frequency differences between aggressive and nonaggressive PCa were not statistically significant: TP53, RAD51D, BARD1, GEN1, and SLX4. Deleterious variants in these 11 candidate genes were carried by 2.3% of patients with nonaggressive, 5.6% with aggressive, and 7.0% with metastatic PCa. Conclusions and Relevance: The findings of this study provide further support for DNA repair and cancer susceptibility genes to better inform disease management in men with PCa and for extending testing to men with nonaggressive disease, as men carrying deleterious alleles in these genes are likely to develop more advanced disease.

Evaluating Approaches for Constructing Polygenic Risk Scores for Prostate Cancer in Men of African and European Ancestry.

Genome-wide polygenic risk scores (GW-PRS) have been reported to have better predictive ability than PRS based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer risk variants from multi-ancestry GWAS and fine-mapping studies (PRS 269 ). GW-PRS models were trained using a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls used to develop the multi-ancestry PRS 269 . Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California/Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI=0.635-0.677) in African and 0.844 (95% CI=0.840-0.848) in European ancestry men and corresponding prostate cancer OR of 1.83 (95% CI=1.67-2.00) and 2.19 (95% CI=2.14-2.25), respectively, for each SD unit increase in the GW-PRS. However, compared to the GW-PRS, in African and European ancestry men, the PRS 269 had larger or similar AUCs (AUC=0.679, 95% CI=0.659-0.700 and AUC=0.845, 95% CI=0.841-0.849, respectively) and comparable prostate cancer OR (OR=2.05, 95% CI=1.87-2.26 and OR=2.21, 95% CI=2.16-2.26, respectively). Findings were similar in the validation data. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the multi-ancestry PRS 269 constructed with fine-mapping.

Evaluating approaches for constructing polygenic risk scores for prostate cancer in men of African and European ancestry.

Genome-wide polygenic risk scores (GW-PRSs) have been reported to have better predictive ability than PRSs based on genome-wide significance thresholds across numerous traits. We compared the predictive ability of several GW-PRS approaches to a recently developed PRS of 269 established prostate cancer-risk variants from multi-ancestry GWASs and fine-mapping studies (PRS269). GW-PRS models were trained with a large and diverse prostate cancer GWAS of 107,247 cases and 127,006 controls that we previously used to develop the multi-ancestry PRS269. Resulting models were independently tested in 1,586 cases and 1,047 controls of African ancestry from the California Uganda Study and 8,046 cases and 191,825 controls of European ancestry from the UK Biobank and further validated in 13,643 cases and 210,214 controls of European ancestry and 6,353 cases and 53,362 controls of African ancestry from the Million Veteran Program. In the testing data, the best performing GW-PRS approach had AUCs of 0.656 (95% CI = 0.635-0.677) in African and 0.844 (95% CI = 0.840-0.848) in European ancestry men and corresponding prostate cancer ORs of 1.83 (95% CI = 1.67-2.00) and 2.19 (95% CI = 2.14-2.25), respectively, for each SD unit increase in the GW-PRS. Compared to the GW-PRS, in African and European ancestry men, the PRS269 had larger or similar AUCs (AUC = 0.679, 95% CI = 0.659-0.700 and AUC = 0.845, 95% CI = 0.841-0.849, respectively) and comparable prostate cancer ORs (OR = 2.05, 95% CI = 1.87-2.26 and OR = 2.21, 95% CI = 2.16-2.26, respectively). Findings were similar in the validation studies. This investigation suggests that current GW-PRS approaches may not improve the ability to predict prostate cancer risk compared to the PRS269 developed from multi-ancestry GWASs and fine-mapping.

Serum testosterone and prostate cancer in men with germline BRCA1/2 pathogenic variants.

Objectives: The relation of serum androgens and the development of prostate cancer (PCa) is subject of debate. Lower total testosterone (TT) levels have been associated with increased PCa detection and worse pathological features after treatment. However, data from the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) and Prostate Cancer Prevention (PCPT) trial groups indicate no association. The aim of this study is to investigate the association of serum androgen levels and PCa detection in a prospective screening study of men at higher genetic risk of aggressive PCa due to BRCA1/2 pathogenic variants (PVs), the IMPACT study. Methods: Men enrolled in the IMPACT study provided serum samples during regular visits. Hormonal levels were calculated using immunoassays. Free testosterone (FT) was calculated from TT and sex hormone binding globulin (SHBG) using the Sodergard mass equation. Age, body mass index (BMI), prostate-specific antigen (PSA) and hormonal concentrations were compared between genetic cohorts. We also explored associations between age and TT, SHBG, FT and PCa, in the whole subset and stratified by BRCA1/2 PVs status. Results: A total of 777 participants in the IMPACT study had TT and SHBG measurements in serum samples at annual visits, giving 3940 prospective androgen levels, from 266 BRCA1 PVs carriers, 313 BRCA2 PVs carriers and 198 non-carriers. The median number of visits per patient was 5. There was no difference in TT, SHBG and FT between carriers and non-carriers. In a univariate analysis, androgen levels were not associated with PCa. In the analysis stratified by carrier status, no significant association was found between hormonal levels and PCa in non-carriers, BRCA1 or BRCA2 PVs carriers. Conclusions: Male BRCA1/2 PVs carriers have a similar androgen profile to non-carriers. Hormonal levels were not associated with PCa in men with and without BRCA1/2 PVs. Mechanisms related to the particularly aggressive phenotype of PCa in BRCA2 PVs carriers may therefore not be linked with circulating hormonal levels.

Family History of Prostate Cancer and Survival Outcomes in the UK Genetic Prostate Cancer Study.

BACKGROUND: A family history (FH) of prostate cancer (PrCa) is associated with an increased likelihood of PrCa diagnosis. Conflicting evidence exists regarding familial PrCa and clinical outcomes among PrCa patients, including all-cause mortality/overall survival (OS), PrCa-specific survival (PCSS), aggressive histology, and stage at diagnosis. OBJECTIVE: To determine how the number, degree, and age of a PrCa patient's affected relatives are associated with OS and PCSS of those already diagnosed with PrCa. DESIGN, SETTING, AND PARTICIPANTS: The UK Genetic Prostate Cancer Study is a longitudinal, multi-institutional, observational study collecting baseline and follow-up clinical data since 1992. We examined OS and PCSS in 16340 men by degree and number of relatives with prostate and genetically related cancers (breast, ovarian, and colorectal). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was all-cause mortality among PrCa patients. The risk of death with respect to FH was assessed by calculating hazard ratios from Cox proportional hazard regression models, adjusting for relevant factors. RESULTS AND LIMITATIONS: A stronger FH was inversely associated with the risk of all-cause and PrCa-specific mortality. This association was greater in those with an increasing number (p-trend < 0.001) and increasing closeness (p-trend < 0.001) of the diagnosed relatives. Patients with at least one first-degree relative were at a lower risk of all-cause mortality than those with no FH (hazard ratio = 0.82 [95% confidence interval 0.75-0.89]). The population is largely of European ancestry, and this may cause an issue with representation and generalisation. Data are missing on epidemiological risk factors for death such as smoking and on comorbidities. Recall of family members' diagnoses may affect the classification of FH in unconfirmed cases. CONCLUSIONS: Based on the investigation of the type and timing of relatives' cancers, it is likely that reductions in mortality are due almost completely to a greater awareness of the disease. This study provides information for clinicians guiding patients and their relatives based on their familial risk. It shows the importance of screening and awareness programmes, which are likely to improve survival among men with an FH. PATIENT SUMMARY: We were interested in how a family history of prostate cancer affects survival in prostate cancer patients. We studied 16340 patients, categorised them according to the strength of their family history, and found that the stronger their family history, the better they did in terms of overall survival. We looked at the type and timing of patients' diagnoses compared with those of their relatives and found that this effect is likely to be explained by awareness, which indicates the importance of screening and awareness programmes.

CanRisk-Prostate: A Comprehensive, Externally Validated Risk Model for the Prediction of Future Prostate Cancer.

PURPOSE: Prostate cancer (PCa) is highly heritable. No validated PCa risk model currently exists. We therefore sought to develop a genetic risk model that can provide personalized predicted PCa risks on the basis of known moderate- to high-risk pathogenic variants, low-risk common genetic variants, and explicit cancer family history, and to externally validate the model in an independent prospective cohort. MATERIALS AND METHODS: We developed a risk model using a kin-cohort comprising individuals from 16,633 PCa families ascertained in the United Kingdom from 1993 to 2017 from the UK Genetic Prostate Cancer Study, and complex segregation analysis adjusting for ascertainment. The model was externally validated in 170,850 unaffected men (7,624 incident PCas) recruited from 2006 to 2010 to the independent UK Biobank prospective cohort study. RESULTS: The most parsimonious model included the effects of pathogenic variants in BRCA2, HOXB13, and BRCA1, and a polygenic score on the basis of 268 common low-risk variants. Residual familial risk was modeled by a hypothetical recessively inherited variant and a polygenic component whose standard deviation decreased log-linearly with age. The model predicted familial risks that were consistent with those reported in previous observational studies. In the validation cohort, the model discriminated well between unaffected men and men with incident PCas within 5 years (C-index, 0.790; 95% CI, 0.783 to 0.797) and 10 years (C-index, 0.772; 95% CI, 0.768 to 0.777). The 50% of men with highest predicted risks captured 86.3% of PCa cases within 10 years. CONCLUSION: To our knowledge, this is the first validated risk model offering personalized PCa risks. The model will assist in counseling men concerned about their risk and can facilitate future risk-stratified population screening approaches.

Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.93, 95% CI = 0.76-1.13, P = 0.46) or aggressive (aggregate OR = 1.14, 95% CI = 0.92-1.41, P = 0.22) prostate cancer risk. CHIP was weakly associated with genetic risk of overall prostate cancer, measured using a polygenic risk score (OR = 1.05 per unit increase, 95% CI = 1.01-1.10, P = 0.01). CHIP was not significantly associated with carrying pathogenic/likely pathogenic/deleterious variants in DNA repair genes, which have previously been found to be associated with aggressive prostate cancer. While findings from this study suggest that CHIP is likely not a risk factor for prostate cancer, it will be important to investigate other types of CH in association with prostate cancer risk.

Prostate cancer risk in men of differing genetic ancestry and approaches to disease screening and management in these groups.

Prostate cancer is the second most common solid tumour in men worldwide and it is also the most common cancer affecting men of African descent. Prostate cancer incidence and mortality vary across regions and populations. Some of this is explained by a large heritable component of this disease. It has been established that men of African and African Caribbean ethnicity are predisposed to prostate cancer (PrCa) that can have an earlier onset and a more aggressive course, thereby leading to poorer outcomes for patients in this group. Literature searches were carried out using the PubMed, EMBASE and Cochrane Library databases to identify studies associated with PrCa risk and its association with ancestry, screening and management of PrCa. In order to be included, studies were required to be published in English in full-text form. An attractive approach is to identify high-risk groups and develop a targeted screening programme for them as the benefits of population-wide screening in PrCa using prostate-specific antigen (PSA) testing in general population screening have shown evidence of benefit; however, the harms are considered to weigh heavier because screening using PSA testing can lead to over-diagnosis and over-treatment. The aim of targeted screening of higher-risk groups identified by genetic risk stratification is to reduce over-diagnosis and treat those who are most likely to benefit.

Trans-ancestry genome-wide association meta-analysis of prostate cancer identifies new susceptibility loci and informs genetic risk prediction.

Prostate cancer is a highly heritable disease with large disparities in incidence rates across ancestry populations. We conducted a multiancestry meta-analysis of prostate cancer genome-wide association studies (107,247 cases and 127,006 controls) and identified 86 new genetic risk variants independently associated with prostate cancer risk, bringing the total to 269 known risk variants. The top genetic risk score (GRS) decile was associated with odds ratios that ranged from 5.06 (95% confidence interval (CI), 4.84-5.29) for men of European ancestry to 3.74 (95% CI, 3.36-4.17) for men of African ancestry. Men of African ancestry were estimated to have a mean GRS that was 2.18-times higher (95% CI, 2.14-2.22), and men of East Asian ancestry 0.73-times lower (95% CI, 0.71-0.76), than men of European ancestry. These findings support the role of germline variation contributing to population differences in prostate cancer risk, with the GRS offering an approach for personalized risk prediction.

Rare Germline Variants in ATM Predispose to Prostate Cancer: A PRACTICAL Consortium Study.

BACKGROUND: Germline ATM mutations are suggested to contribute to predisposition to prostate cancer (PrCa). Previous studies have had inadequate power to estimate variant effect sizes. OBJECTIVE: To precisely estimate the contribution of germline ATM mutations to PrCa risk. DESIGN, SETTING, AND PARTICIPANTS: We analysed next-generation sequencing data from 13 PRACTICAL study groups comprising 5560 cases and 3353 controls of European ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variant Call Format files were harmonised, annotated for rare ATM variants, and classified as tier 1 (likely pathogenic) or tier 2 (potentially deleterious). Associations with overall PrCa risk and clinical subtypes were estimated. RESULTS AND LIMITATIONS: PrCa risk was higher in carriers of a tier 1 germline ATM variant, with an overall odds ratio (OR) of 4.4 (95% confidence interval [CI]: 2.0-9.5). There was also evidence that PrCa cases with younger age at diagnosis (<65 yr) had elevated tier 1 variant frequencies (pdifference = 0.04). Tier 2 variants were also associated with PrCa risk, with an OR of 1.4 (95% CI: 1.1-1.7). CONCLUSIONS: Carriers of pathogenic ATM variants have an elevated risk of developing PrCa and are at an increased risk for earlier-onset disease presentation. These results provide information for counselling of men and their families. PATIENT SUMMARY: In this study, we estimated that men who inherit a likely pathogenic mutation in the ATM gene had an approximately a fourfold risk of developing prostate cancer. In addition, they are likely to develop the disease earlier.

Germline Sequencing DNA Repair Genes in 5545 Men With Aggressive and Nonaggressive Prostate Cancer.

BACKGROUND: There is an urgent need to identify factors specifically associated with aggressive prostate cancer (PCa) risk. We investigated whether rare pathogenic, likely pathogenic, or deleterious (P/LP/D) germline variants in DNA repair genes are associated with aggressive PCa risk in a case-case study of aggressive vs nonaggressive disease. METHODS: Participants were 5545 European-ancestry men, including 2775 nonaggressive and 2770 aggressive PCa cases, which included 467 metastatic cases (16.9%). Samples were assembled from 12 international studies and germline sequenced together. Rare (minor allele frequency < 0.01) P/LP/D variants were analyzed for 155 DNA repair genes. We compared single variant, gene-based, and DNA repair pathway-based burdens by disease aggressiveness. All statistical tests are 2-sided. RESULTS: BRCA2 and PALB2 had the most statistically significant gene-based associations, with 2.5% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D BRCA2 alleles (odds ratio [OR] = 3.19, 95% confidence interval [CI] = 1.94 to 5.25, P = 8.58 × 10-7) and 0.65% of aggressive and 0.11% of nonaggressive cases carrying P/LP/D PALB2 alleles (OR = 6.31, 95% CI = 1.83 to 21.68, P = 4.79 × 10-4). ATM had a nominal association, with 1.6% of aggressive and 0.8% of nonaggressive cases carrying P/LP/D ATM alleles (OR = 1.88, 95% CI = 1.10 to 3.22, P = .02). In aggregate, P/LP/D alleles within 24 literature-curated candidate PCa DNA repair genes were more common in aggressive than nonaggressive cases (carrier frequencies = 14.2% vs 10.6%, respectively; P = 5.56 × 10-5). However, this difference was non-statistically significant (P = .18) on excluding BRCA2, PALB2, and ATM. Among these 24 genes, P/LP/D carriers had a 1.06-year younger diagnosis age (95% CI = -1.65 to 0.48, P = 3.71 × 10-4). CONCLUSIONS: Risk conveyed by DNA repair genes is largely driven by rare P/LP/D alleles within BRCA2, PALB2, and ATM. These findings support the importance of these genes in both screening and disease management considerations.

Relationship of self-reported body size and shape with risk for prostate cancer: A UK case-control study.

INTRODUCTION: Previous evidence has suggested a relationship between male self-reported body size and the risk of developing prostate cancer. In this UK-wide case-control study, we have explored the possible association of prostate cancer risk with male self-reported body size. We also investigated body shape as a surrogate marker for fat deposition around the body. As obesity and excessive adiposity have been linked with increased risk for developing a number of different cancers, further investigation of self-reported body size and shape and their potential relationship with prostate cancer was considered to be appropriate. OBJECTIVE: The study objective was to investigate whether underlying associations exist between prostate cancer risk and male self-reported body size and shape. METHODS: Data were collected from a large case-control study of men (1928 cases and 2043 controls) using self-administered questionnaires. Data from self-reported pictograms of perceived body size relating to three decades of life (20's, 30's and 40's) were recorded and analysed, including the pattern of change. The associations of self-identified body shape with prostate cancer risk were also explored. RESULTS: Self-reported body size for men in their 20's, 30's and 40's did not appear to be associated with prostate cancer risk. More than half of the subjects reported an increase in self-reported body size throughout these three decades of life. Furthermore, no association was observed between self-reported body size changes and prostate cancer risk. Using 'symmetrical' body shape as a reference group, subjects with an 'apple' shape showed a significant 27% reduction in risk (Odds ratio = 0.73, 95% C.I. 0.57-0.92). CONCLUSIONS: Change in self-reported body size throughout early to mid-adulthood in males is not a significant risk factor for the development of prostate cancer. Body shape indicative of body fat distribution suggested that an 'apple' body shape was protective and inversely associated with prostate cancer risk when compared with 'symmetrical' shape. Further studies which investigate prostate cancer risk and possible relationships with genetic factors known to influence body shape may shed further light on any underlying associations.

Correction: Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease.

This article was originally published under the standard License to Publish, but has now been made available under a CC BY 4.0 license. The PDF and HTML versions of the paper have been modified accordingly.

Germline DNA Repair Gene Mutations in Young-onset Prostate Cancer Cases in the UK: Evidence for a More Extensive Genetic Panel.

BACKGROUND: Rare germline mutations in DNA repair genes are associated with prostate cancer (PCa) predisposition and prognosis. OBJECTIVE: To quantify the frequency of germline DNA repair gene mutations in UK PCa cases and controls, in order to more comprehensively evaluate the contribution of individual genes to overall PCa risk and likelihood of aggressive disease. DESIGN, SETTING, AND PARTICIPANTS: We sequenced 167 DNA repair and eight PCa candidate genes in a UK-based cohort of 1281 young-onset PCa cases (diagnosed at ≤60yr) and 1160 selected controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Gene-level SKAT-O and gene-set adaptive combination of p values (ADA) analyses were performed separately for cases versus controls, and aggressive (Gleason score ≥8, n=201) versus nonaggressive (Gleason score ≤7, n=1048) cases. RESULTS AND LIMITATIONS: We identified 233 unique protein truncating variants (PTVs) with minor allele frequency <0.5% in controls in 97 genes. The total proportion of PTV carriers was higher in cases than in controls (15% vs 12%, odds ratio [OR]=1.29, 95% confidence interval [CI] 1.01-1.64, p=0.036). Gene-level analyses selected NBN (pSKAT-O=2.4×10-4) for overall risk and XPC (pSKAT-O=1.6×10-4) for aggressive disease, both at candidate-level significance (p<3.1×10-4 and p<3.4×10-4, respectively). Gene-set analysis identified a subset of 20 genes associated with increased PCa risk (OR=3.2, 95% CI 2.1-4.8, pADA=4.1×10-3) and four genes that increased risk of aggressive disease (OR=11.2, 95% CI 4.6-27.7, pADA=5.6×10-3), three of which overlap the predisposition gene set. CONCLUSIONS: The union of the gene-level and gene-set-level analyses identified 23 unique DNA repair genes associated with PCa predisposition or risk of aggressive disease. These findings will help facilitate the development of a PCa-specific sequencing panel with both predictive and prognostic potential. PATIENT SUMMARY: This large sequencing study assessed the rate of inherited DNA repair gene mutations between prostate cancer patients and disease-free men. A panel of 23 genes was identified, which may improve risk prediction or treatment pathways in future clinical practice.

Author Correction: Germline variation at 8q24 and prostate cancer risk in men of European ancestry.

The original version of this Article contained an error in the spelling of the author Manuela Gago-Dominguez, which was incorrectly given as Manuela G. Dominguez. This has now been corrected in both the PDF and HTML versions of the Article.

Author Correction: Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.

In the version of this article initially published, the name of author Manuela Gago-Dominguez was misspelled as Manuela Gago Dominguez. The error has been corrected in the HTML and PDF version of the article.

Homeobox B13 G84E Mutation and Prostate Cancer Risk.

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.