Germline Genetic Variants Associated with Somatic TMPRSS2:ERG Fusion Status in Prostate Cancer: A Genome-Wide Association Study.

BACKGROUND: The prostate cancer subtype defined by the presence of TMPRSS2:ERG has been shown to be molecularly and epidemiologically distinct. However, few studies have investigated germline genetic variants associating with TMPRSS2:ERG fusion status. METHODS: We performed a genome-wide association study with 396 TMPRSS2:ERG(+) cases, 390 TMPRSS2:ERG(-) cases, and 2,386 cancer-free controls from the Physicians' Health Study (PHS), the Health Professionals Follow-up Study (HPFS), and a Seattle-based Fred Hutchinson (FH) Cancer Center Prostate Cancer Study. We applied logistic regression models to test the associations between ∼5 million SNPs with TMPRSS2:ERG fusion status accounting for population stratification. RESULTS: We did not identify genome-wide significant variants comparing the TMPRSS2:ERG(+) to the TMPRSS2:ERG(-) prostate cancer cases in the meta-analysis. When comparing TMPRSS2:ERG(+) prostate cancer cases with controls without prostate cancer, 10 genome-wide significant SNPs on chromosome 17q24.3 were observed in the meta-analysis. When comparing TMPRSS2:ERG(-) prostate cancer cases with controls without prostate cancer, two SNPs on chromosome 8q24.21 in the meta-analysis reached genome-wide significance. CONCLUSIONS: We observed SNPs at several known prostate cancer risk loci (17q24.3, 1q32.1, and 8q24.21) that were differentially and exclusively associated with the risk of developing prostate tumors either with or without the gene fusion. IMPACT: Our findings suggest that tumors with the TMPRSS2:ERG fusion exhibit a different germline genetic etiology compared with fusion negative cases.

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.

Biochemical activity induced by a germline variation in KLK3 (PSA) associates with cellular function and clinical outcome in prostate cancer.

Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility. The non-synonymous KLK3 SNP, rs17632542 (c.536T>C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity as a previously undescribed function mediating prostate cancer pathogenesis. The 'Thr' PSA variant led to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displayed higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterization of this PSA variant demonstrated markedly reduced proteolytic activity that correlated with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele had reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.

Evidence of Novel Susceptibility Variants for Prostate Cancer and a Multiancestry Polygenic Risk Score Associated with Aggressive Disease in Men of African Ancestry.

BACKGROUND: Genetic factors play an important role in prostate cancer (PCa) susceptibility. OBJECTIVE: To discover common genetic variants contributing to the risk of PCa in men of African ancestry. DESIGN, SETTING, AND PARTICIPANTS: We conducted a meta-analysis of ten genome-wide association studies consisting of 19378 cases and 61620 controls of African ancestry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Common genotyped and imputed variants were tested for their association with PCa risk. Novel susceptibility loci were identified and incorporated into a multiancestry polygenic risk score (PRS). The PRS was evaluated for associations with PCa risk and disease aggressiveness. RESULTS AND LIMITATIONS: Nine novel susceptibility loci for PCa were identified, of which seven were only found or substantially more common in men of African ancestry, including an African-specific stop-gain variant in the prostate-specific gene anoctamin 7 (ANO7). A multiancestry PRS of 278 risk variants conferred strong associations with PCa risk in African ancestry studies (odds ratios [ORs] >3 and >5 for men in the top PRS decile and percentile, respectively). More importantly, compared with men in the 40-60% PRS category, men in the top PRS decile had a significantly higher risk of aggressive PCa (OR = 1.23, 95% confidence interval = 1.10-1.38, p = 4.4 × 10-4). CONCLUSIONS: This study demonstrates the importance of large-scale genetic studies in men of African ancestry for a better understanding of PCa susceptibility in this high-risk population and suggests a potential clinical utility of PRS in differentiating between the risks of developing aggressive and nonaggressive disease in men of African ancestry. PATIENT SUMMARY: In this large genetic study in men of African ancestry, we discovered nine novel prostate cancer (PCa) risk variants. We also showed that a multiancestry polygenic risk score was effective in stratifying PCa risk, and was able to differentiate risk of aggressive and nonaggressive disease.

Coffee Intake, Caffeine Metabolism Genotype, and Survival Among Men with Prostate Cancer.

BACKGROUND: Coffee intake may lower prostate cancer risk and progression, but postdiagnosis outcomes by caffeine metabolism genotype are not well characterized. OBJECTIVE: To evaluate associations between coffee intake, caffeine metabolism genotype, and survival in a large, multicenter study of men with prostate cancer. DESIGN, SETTING, AND PARTICIPANTS: Data from The PRACTICAL Consortium database for 5727 men with prostate cancer from seven US, Australian, and European studies were included. The cases included had data available for the CYP1A2 -163C>A rs762551 single-nucleotide variant associated with caffeine metabolism, coffee intake, and >6 mo of follow-up. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable-adjusted Cox proportional hazards models across pooled patient-level data were used to compare the effect of coffee intake (categorized as low [reference], high, or none/very low) in relation to overall survival (OS) and prostate cancer-specific survival (PCSS), with stratified analyses conducted by clinical disease risk and genotype. RESULTS AND LIMITATIONS: High coffee intake appeared to be associated with longer PCSS (hazard ratio [HR] 0.85, 95% confidence interval [CI] 0.68-1.08; p = 0.18) and OS (HR 0.90, 95% CI 0.77-1.07; p = 0.24), although results were not statistically significant. In the group with clinically localized disease, high coffee intake was associated with longer PCSS (HR 0.66, 95% CI 0.44-0.98; p = 0.040), with comparable results for the group with advanced disease (HR 0.92, 95% CI 0.69-1.23; p = 0.6). High coffee intake was associated with longer PCSS among men with the CYP1A2 AA (HR 0.67, 95% CI 0.49-0.93; p = 0.017) but not the AC/CC genotype (p = 0.8); an interaction was detected (p = 0.042). No associations with OS were observed in subgroup analyses (p > 0.05). Limitations include the nominal statistical significance and residual confounding. CONCLUSIONS: Coffee intake was associated with longer PCSS among men with a CYP1A2 -163AA (*1F/*1F) genotype, a finding that will require further replication. PATIENT SUMMARY: It is likely that coffee intake is associated with longer prostate cancer-specific survival in certain groups, but more research is needed to fully understand which men may benefit and why.

Methylation Subtypes of Primary Prostate Cancer Predict Poor Prognosis.

BACKGROUND: Patients with prostate cancer experience heterogeneous outcomes after radical prostatectomy. Genomic studies including The Cancer Genome Atlas (TCGA) have reported molecular signatures of prostate cancer, but few studies have assessed the prognostic effects of DNA methylation profiles. METHODS: We conducted the largest methylome subtyping analysis for primary prostate tumors to date, using methylome data from three patient populations: TCGA, a prostate cancer cohort study conducted at the Fred Hutchinson Cancer Research Center (FH; Seattle, WA), and the Canadian International Cancer Genome Consortium (ICGC) cohort. Four subtypes were detected in the TCGA dataset, then independently assigned to FH and ICGC cohort data. The identified methylation subtypes were assessed for association with cancer prognosis in the above three patient populations. RESULTS: Using a set of hypermethylated CpG sites, four methylation subtypes were identified in TCGA. Compared with subtype 1, subtype 4 had an HR of 2.09 (P = 0.029) for biochemical recurrence (BCR) in TCGA patients. HRs of 2.76 (P = 0.002) for recurrence and 9.73 (P = 0.002) for metastatic-lethal (metastasis or prostate cancer-specific death) outcomes were observed in the FH cohort. A similar pattern of association was noted in the Canadian ICGC cohort, though HRs were not statistically significant. CONCLUSIONS: A hypermethylated subtype was associated with an increased hazard of recurrence and mortality in three studies with prostate tumor methylome data. Further molecular work is needed to understand the effect of methylation subtypes on cancer prognosis. IMPACT: This study identified a DNA methylation subtype that was associated with worse prostate cancer prognosis after radical prostatectomy.

A multiple-testing procedure for high-dimensional mediation hypotheses.

Mediation analysis is of rising interest in epidemiology and clinical trials. Among existing methods, the joint significance (JS) test yields an overly conservative type I error rate and low power, particularly for high-dimensional mediation hypotheses. In this article we develop a multiple-testing procedure that accurately controls the family-wise error rate (FWER) and the false discovery rate (FDR) when testing high-dimensional mediation hypotheses. The core of our procedure is based on estimating the proportions of component null hypotheses and the underlying mixture null distribution of p-values. Theoretical developments and simulation experiments prove that the proposed procedure effectively controls FWER and FDR. Two mediation analyses on DNA methylation and cancer research are presented: assessing the mediation role of DNA methylation in genLetic regulation of gene expression in primary prostate cancer samples; exploring the possibility of DNA methylation mediating the effect of exercise on prostate cancer progression. Results of data examples include wellL-behaved quantile-quantile plots and improved power to detect novel mediation relationships. An R package HDMT implementing the proposed procedure is freely accessible in CRAN.

Prostate cancer risk stratification improvement across multiple ancestries with new polygenic hazard score.

BACKGROUND: Prostate cancer risk stratification using single-nucleotide polymorphisms (SNPs) demonstrates considerable promise in men of European, Asian, and African genetic ancestries, but there is still need for increased accuracy. We evaluated whether including additional SNPs in a prostate cancer polygenic hazard score (PHS) would improve associations with clinically significant prostate cancer in multi-ancestry datasets. METHODS: In total, 299 SNPs previously associated with prostate cancer were evaluated for inclusion in a new PHS, using a LASSO-regularized Cox proportional hazards model in a training dataset of 72,181 men from the PRACTICAL Consortium. The PHS model was evaluated in four testing datasets: African ancestry, Asian ancestry, and two of European Ancestry-the Cohort of Swedish Men (COSM) and the ProtecT study. Hazard ratios (HRs) were estimated to compare men with high versus low PHS for association with clinically significant, with any, and with fatal prostate cancer. The impact of genetic risk stratification on the positive predictive value (PPV) of PSA testing for clinically significant prostate cancer was also measured. RESULTS: The final model (PHS290) had 290 SNPs with non-zero coefficients. Comparing, for example, the highest and lowest quintiles of PHS290, the hazard ratios (HRs) for clinically significant prostate cancer were 13.73 [95% CI: 12.43-15.16] in ProtecT, 7.07 [6.58-7.60] in African ancestry, 10.31 [9.58-11.11] in Asian ancestry, and 11.18 [10.34-12.09] in COSM. Similar results were seen for association with any and fatal prostate cancer. Without PHS stratification, the PPV of PSA testing for clinically significant prostate cancer in ProtecT was 0.12 (0.11-0.14). For the top 20% and top 5% of PHS290, the PPV of PSA testing was 0.19 (0.15-0.22) and 0.26 (0.19-0.33), respectively. CONCLUSIONS: We demonstrate better genetic risk stratification for clinically significant prostate cancer than prior versions of PHS in multi-ancestry datasets. This is promising for implementing precision-medicine approaches to prostate cancer screening decisions in diverse populations.

Genetic Factors Associated with Prostate Cancer Conversion from Active Surveillance to Treatment.

Men diagnosed with low-risk prostate cancer (PC) are increasingly electing active surveillance (AS) as their initial management strategy. While this may reduce the side effects of treatment for prostate cancer, many men on AS eventually convert to active treatment. PC is one of the most heritable cancers, and genetic factors that predispose to aggressive tumors may help distinguish men who are more likely to discontinue AS. To investigate this, we undertook a multi-institutional genome-wide association study (GWAS) of 5,222 PC patients and 1,139 other patients from replication cohorts, all of whom initially elected AS and were followed over time for the potential outcome of conversion from AS to active treatment. In the GWAS we detected 18 variants associated with conversion, 15 of which were not previously associated with PC risk. With a transcriptome-wide association study (TWAS), we found two genes associated with conversion (MAST3, p = 6.9×10-7 and GAB2, p = 2.0×10-6). Moreover, increasing values of a previously validated 269-variant genetic risk score (GRS) for PC was positively associated with conversion (e.g., comparing the highest to the two middle deciles gave a hazard ratio [HR] = 1.13; 95% Confidence Interval [CI]= 0.94-1.36); whereas, decreasing values of a 36-variant GRS for prostate-specific antigen (PSA) levels were positively associated with conversion (e.g., comparing the lowest to the two middle deciles gave a HR = 1.25; 95% CI, 1.04-1.50). These results suggest that germline genetics may help inform and individualize the decision of AS-or the intensity of monitoring on AS-versus treatment for the initial management of patients with low-risk PC.

Marital status and prostate cancer incidence: a pooled analysis of 12 case-control studies from the PRACTICAL consortium.

While being in a committed relationship is associated with a better prostate cancer prognosis, little is known about how marital status relates to its incidence. Social support provided by marriage/relationship could promote a healthy lifestyle and an increased healthcare seeking behavior. We investigated the association between marital status and prostate cancer risk using data from the PRACTICAL Consortium. Pooled analyses were conducted combining 12 case-control studies based on histologically-confirmed incident prostate cancers and controls with information on marital status prior to diagnosis/interview. Marital status was categorized as married/partner, separated/divorced, single, or widowed. Tumours with Gleason scores ≥ 8 defined high-grade cancers, and low-grade otherwise. NCI-SEER's summary stages (local, regional, distant) indicated the extent of the cancer. Logistic regression was used to derive odds ratios (ORs) and 95% confidence intervals (CI) for the association between marital status and prostate cancer risk, adjusting for potential confounders. Overall, 14,760 cases and 12,019 controls contributed to analyses. Compared to men who were married/with a partner, widowed men had an OR of 1.19 (95% CI 1.03-1.35) of prostate cancer, with little difference between low- and high-grade tumours. Risk estimates among widowers were 1.14 (95% CI 0.97-1.34) for local, 1.53 (95% CI 1.22-1.92) for regional, and 1.56 (95% CI 1.05-2.32) for distant stage tumours. Single men had elevated risks of high-grade cancers. Our findings highlight elevated risks of incident prostate cancer among widowers, more often characterized by tumours that had spread beyond the prostate at the time of diagnosis. Social support interventions and closer medical follow-up in this sub-population are warranted.

A polymorphism in the promoter of FRAS1 is a candidate SNP associated with metastatic prostate cancer.

BACKGROUND: Inflammation and one of its mediators, NF-kappa B (NFκB), have been implicated in prostate cancer carcinogenesis. We assessed whether germline polymorphisms associated with NFκB are associated with the risk of developing lethal disease (metastases or death from prostate cancer). METHODS: Using a Bayesian approach leveraging NFκB biology with integration of publicly available datasets we used a previously defined genome-wide functional association network specific to NFκB and lethal prostate cancer. A dense-module-searching method identified modules enriched with significant genes from a genome-wide association study (GWAS) study in a discovery data set, Physicians' Health Study and Health Professionals Follow-up Study (PHS/HPFS). The top 48 candidate single nucleotide polymorphisms (SNPs) from the dense-module-searching method were then assessed in an independent prostate cancer cohort and the one SNP reproducibly associated with lethality was tested in a third cohort. Logistic regression models evaluated the association between each SNP and lethal prostate cancer. The candidate SNP was assessed for association with lethal prostate cancer in 6 of 28 studies in the prostate cancer association group to investigate cancer associated alterations in the genome (PRACTICAL) Consortium where there was some medical record review for death ascertainment which also had SNP data from the ONCOARRAY platform. All men self-identified as Caucasian. RESULTS: The rs1910301 SNP which was reproducibly associated with lethal disease was nominally associated with lethal disease (odds ratio [OR] = 1.40; p = .02) in the discovery cohort and the minor allele was also associated with lethal disease in two independent cohorts (OR = 1.35; p = .04 and OR = 1.35; p = .07). Fixed effects meta-analysis of all three cohorts found an association: OR = 1.37 (95% confidence interval [CI]: 1.15-1.62, p = .0003). This SNP is in the promoter region of FRAS1, a gene involved in epidermal-basement membrane adhesion and is present at a higher frequency in men with African ancestry. No association was found in the subset of studies from the PRACTICAL consortium studies which had a total of 106 deaths out total of 3263 patients and a median follow-up of 4.4 years. CONCLUSIONS: Through its connection with the NFκB pathway, a candidate SNP with a higher frequency in men of African ancestry without cancer was found to be associated with lethal prostate cancer across three well-annotated independent cohorts of Caucasian men.

A rare variant in EZH2 is associated with prostate cancer risk.

Prostate cancer (PrCa) is highly heritable, and although rare variants contribute significantly to PrCa risk, few have been identified to date. Herein, whole-genome sequencing was performed in a large PrCa family featuring multiple affected relatives spanning several generations. A rare, predicted splice site EZH2 variant, rs78589034 (G > A), was identified as segregating with disease in all but two individuals in the family, one of whom was affected with lymphoma and bowel cancer and a female relative. This variant was significantly associated with disease risk in combined familial and sporadic PrCa datasets (n = 1551; odds ratio [OR] = 3.55, P = 1.20 × 10-5 ). Transcriptome analysis was performed on prostate tumour needle biopsies available for two rare variant carriers and two wild-type cases. Although no allele-dependent differences were detected in EZH2 transcripts, a distinct differential gene expression signature was observed when comparing prostate tissue from the rare variant carriers with the wild-type samples. The gene expression signature comprised known downstream targets of EZH2 and included the top-ranked genes, DUSP1, FOS, JUNB and EGR1, which were subsequently validated by qPCR. These data provide evidence that rs78589034 is associated with increased PrCa risk in Tasmanian men and further, that this variant may be associated with perturbed EZH2 function in prostate tissue. Disrupted EZH2 function is a driver of tumourigenesis in several cancers, including prostate, and is of significant interest as a therapeutic target.

KLK3 SNP-SNP interactions for prediction of prostate cancer aggressiveness.

Risk classification for prostate cancer (PCa) aggressiveness and underlying mechanisms remain inadequate. Interactions between single nucleotide polymorphisms (SNPs) may provide a solution to fill these gaps. To identify SNP-SNP interactions in the four pathways (the angiogenesis-, mitochondria-, miRNA-, and androgen metabolism-related pathways) associated with PCa aggressiveness, we tested 8587 SNPs for 20,729 cases from the PCa consortium. We identified 3 KLK3 SNPs, and 1083 (P < 3.5 × 10-9) and 3145 (P < 1 × 10-5) SNP-SNP interaction pairs significantly associated with PCa aggressiveness. These SNP pairs associated with PCa aggressiveness were more significant than each of their constituent SNP individual effects. The majority (98.6%) of the 3145 pairs involved KLK3. The 3 most common gene-gene interactions were KLK3-COL4A1:COL4A2, KLK3-CDH13, and KLK3-TGFBR3. Predictions from the SNP interaction-based polygenic risk score based on 24 SNP pairs are promising. The prevalence of PCa aggressiveness was 49.8%, 21.9%, and 7.0% for the PCa cases from our cohort with the top 1%, middle 50%, and bottom 1% risk profiles. Potential biological functions of the identified KLK3 SNP-SNP interactions were supported by gene expression and protein-protein interaction results. Our findings suggest KLK3 SNP interactions may play an important role in PCa aggressiveness.

Polygenic hazard score is associated with prostate cancer in multi-ethnic populations.

Genetic models for cancer have been evaluated using almost exclusively European data, which could exacerbate health disparities. A polygenic hazard score (PHS1) is associated with age at prostate cancer diagnosis and improves screening accuracy in Europeans. Here, we evaluate performance of PHS2 (PHS1, adapted for OncoArray) in a multi-ethnic dataset of 80,491 men (49,916 cases, 30,575 controls). PHS2 is associated with age at diagnosis of any and aggressive (Gleason score ≥ 7, stage T3-T4, PSA ≥ 10 ng/mL, or nodal/distant metastasis) cancer and prostate-cancer-specific death. Associations with cancer are significant within European (n = 71,856), Asian (n = 2,382), and African (n = 6,253) genetic ancestries (p < 10-180). Comparing the 80th/20th PHS2 percentiles, hazard ratios for prostate cancer, aggressive cancer, and prostate-cancer-specific death are 5.32, 5.88, and 5.68, respectively. Within European, Asian, and African ancestries, hazard ratios for prostate cancer are: 5.54, 4.49, and 2.54, respectively. PHS2 risk-stratifies men for any, aggressive, and fatal prostate cancer in a multi-ethnic dataset.

Additional SNPs improve risk stratification of a polygenic hazard score for prostate cancer.

BACKGROUND: Polygenic hazard scores (PHS) can identify individuals with increased risk of prostate cancer. We estimated the benefit of additional SNPs on performance of a previously validated PHS (PHS46). MATERIALS AND METHOD: 180 SNPs, shown to be previously associated with prostate cancer, were used to develop a PHS model in men with European ancestry. A machine-learning approach, LASSO-regularized Cox regression, was used to select SNPs and to estimate their coefficients in the training set (75,596 men). Performance of the resulting model was evaluated in the testing/validation set (6,411 men) with two metrics: (1) hazard ratios (HRs) and (2) positive predictive value (PPV) of prostate-specific antigen (PSA) testing. HRs were estimated between individuals with PHS in the top 5% to those in the middle 40% (HR95/50), top 20% to bottom 20% (HR80/20), and bottom 20% to middle 40% (HR20/50). PPV was calculated for the top 20% (PPV80) and top 5% (PPV95) of PHS as the fraction of individuals with elevated PSA that were diagnosed with clinically significant prostate cancer on biopsy. RESULTS: 166 SNPs had non-zero coefficients in the Cox model (PHS166). All HR metrics showed significant improvements for PHS166 compared to PHS46: HR95/50 increased from 3.72 to 5.09, HR80/20 increased from 6.12 to 9.45, and HR20/50 decreased from 0.41 to 0.34. By contrast, no significant differences were observed in PPV of PSA testing for clinically significant prostate cancer. CONCLUSIONS: Incorporating 120 additional SNPs (PHS166 vs PHS46) significantly improved HRs for prostate cancer, while PPV of PSA testing remained the same.

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.

Two-stage Study of Familial Prostate Cancer by Whole-exome Sequencing and Custom Capture Identifies 10 Novel Genes Associated with the Risk of Prostate Cancer.

BACKGROUND: Family history of prostate cancer (PCa) is a well-known risk factor, and both common and rare genetic variants are associated with the disease. OBJECTIVE: To detect new genetic variants associated with PCa, capitalizing on the role of family history and more aggressive PCa. DESIGN, SETTING, AND PARTICIPANTS: A two-stage design was used. In stage one, whole-exome sequencing was used to identify potential risk alleles among affected men with a strong family history of disease or with more aggressive disease (491 cases and 429 controls). Aggressive disease was based on a sum of scores for Gleason score, node status, metastasis, tumor stage, prostate-specific antigen at diagnosis, systemic recurrence, and time to PCa death. Genes identified in stage one were screened in stage two using a custom-capture design in an independent set of 2917 cases and 1899 controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Frequencies of genetic variants (singly or jointly in a gene) were compared between cases and controls. RESULTS AND LIMITATIONS: Eleven genes previously reported to be associated with PCa were detected (ATM, BRCA2, HOXB13, FAM111A, EMSY, HNF1B, KLK3, MSMB, PCAT1, PRSS3, and TERT), as well as an additional 10 novel genes (PABPC1, QK1, FAM114A1, MUC6, MYCBP2, RAPGEF4, RNASEH2B, ULK4, XPO7, and THAP3). Of these 10 novel genes, all but PABPC1 and ULK4 were primarily associated with the risk of aggressive PCa. CONCLUSIONS: Our approach demonstrates the advantage of gene sequencing in the search for genetic variants associated with PCa and the benefits of sampling patients with a strong family history of disease or an aggressive form of disease. PATIENT SUMMARY: Multiple genes are associated with prostate cancer (PCa) among men with a strong family history of this disease or among men with an aggressive form of PCa.