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BACKGROUND: Artificial intelligence (AI) may improve cancer detection and risk prediction during mammography screening, but radiologists' preferences regarding its characteristics and implementation are unknown. PURPOSE: To quantify how different attributes of AI-based cancer detection and risk prediction tools affect radiologists' intentions to use AI during screening mammography interpretation. MATERIALS AND METHODS: Through qualitative interviews with radiologists, we identified five primary attributes for AI-based breast cancer detection and four for breast cancer risk prediction. We developed a discrete choice experiment based on these attributes and invited 150 US-based radiologists to participate. Each respondent made eight choices for each tool between three alternatives: two hypothetical AI-based tools versus screening without AI. We analyzed samplewide preferences using random parameters logit models and identified subgroups with latent class models. RESULTS: Respondents (n = 66; 44% response rate) were from six diverse practice settings across eight states. Radiologists were more interested in AI for cancer detection when sensitivity and specificity were balanced (94% sensitivity with

Background: One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed.Methods: We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined.Results: During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 × 10−6), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 × 10−4). DNA methylation profiles did not differ by recurrence status for the other genes.Conclusions: These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence.Impact: Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence. Cancer Epidemiol Biomarkers Prev; 23(7); 1331–9. ©2014 AACR.

Purpose: Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential.Experimental Design: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum.Results: Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P < 0.05) AUC (range, 0.66–0.75) or pAUC (range, 0.007–0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86–0.89; all P Conclusions: Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311–9. ©2016 AACR.

PDF file - 57K, Genes with over 50% of the 5' region CpG sites having higher methylation in tumor tissue from prostate cancer patients with recurrence versus no recurrence.

Number of time the 42 DNA methylation biomarkers were selected in the bootstrap samples

Background: Chronic inflammation is an important mechanism for the development and progression of prostate cancer (PC). To better understand the potential relationship between genes in the inflammation pathway and PC risk, we evaluated variants in 16 candidate genes.Methods: A total of 143 tagging and amino acid altering single nucleotide polymorphisms (SNPs) were genotyped in Caucasian and African American men participating in one of two population-based, case–control studies (n = 1,458 cases and 1,351 controls). The relative risk of PC was estimated using logistic and polytomous regression models.Results: Ten SNPs in seven genes (CXCL12, IL4, IL6, IL6ST, PTGS2, STAT3, and TNF) were nominally associated (P < 0.05) with risk of PC in Caucasians. The most significant effect on risk was seen with rs11574783 in the interleukin 6 signal transducer (IL6ST) gene (OR = 0.08, 95% CI: 0.01–0.63). Cumulatively, four SNPs in genes interleukin 4 (IL4), IL6ST, PTGS2, and signal transducer and activator of transcription 3 (STAT3) conferred a three-fold elevation in PC risk among men carrying the maximum number of high-risk alleles (OR = 2.97, 95% CI: 1.41–6.25, Ptrend = 0.0003). Risk estimates for seven SNPs varied significantly according to disease aggressiveness (Phomogeneity < 0.05), with SNPs in AKT1, PIK3R1, and STAT3 independently associated with more aggressive PC; OR = 5.1 (95% CI: 2.29–11.40, Ptrend = 3.8 × 10−5) for carriers of all high-risk genotypes.Conclusions: These results suggest that variants in genes within the inflammation pathway may play a role in the development of PC, however, further studies are needed to replicate our findings.Impact: These results underline the potential importance of the inflammation pathway in PC development and progression. Cancer Epidemiol Biomarkers Prev; 20(5); 923–33. ©2011 AACR.

Supplementary Table 1 from Genetic Polymorphisms in Inflammation Pathway Genes and Prostate Cancer Risk

Background: Rare, inherited mutations account for 5% to 10% of all prostate cancer cases. However, to date, few causative mutations have been identified.Methods: To identify rare mutations for prostate cancer, we conducted whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early-onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 prostate cancer cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case–control study (n = 1,155 incident prostate cancer cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry.Results: The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated prostate cancer risk in the population-based study (rs41441651: OR, 2.7; 95% CI, 1.27–5.87; P = 0.010; rs28362675: OR, 2.5; 95% CI, 1.16–5.46; P = 0.019).Conclusions: Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer.Impact: Results implicate BTNL2 as a novel prostate cancer susceptibility gene. Cancer Epidemiol Biomarkers Prev; 22(9); 1520–8. ©2013 AACR.

PDF - 59K, Legend for Supplementary Figure 1.

PDF - 51K, Summary of the whole-exome sequencing statistics for the 91 members of 19 hereditary prostate cancer families.

XLS file - 88K

PDF - 61K, Information on the 22 insertion/deletions identified by whole-exome sequencing.

PDF - 109K, Information on the 174 single nucleotide variants identified by whole-exome sequencing.

Background: Prostate cancer is the second leading cause of cancer-related deaths in men, accounting for more than 30,000 deaths annually. The purpose of this study was to test whether variation in selected candidate genes in biological pathways of interest for prostate cancer progression could help distinguish patients at higher risk for fatal prostate cancer.Methods: In this hypothesis-driven study, we genotyped 937 single nucleotide polymorphisms (SNPs) in 156 candidate genes in a population-based cohort of 1,309 prostate cancer patients. We identified 22 top-ranking SNPs (P ≤ 0.01, FDR ≤ 0.70) associated with prostate cancer-specific mortality (PCSM). A subsequent validation study was completed in an independent population-based cohort of 2,875 prostate cancer patients.Results: Five SNPs were validated (P ≤ 0.05) as being significantly associated with PCSM, one each in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes. Compared with patients with 0 to 2 of the at-risk genotypes those with 4 to 5 at-risk genotypes had a 50% (95% CI, 1.2–1.9) higher risk of PCSM and risk increased with the number of at-risk genotypes carried (Ptrend = 0.001), adjusting for clinicopathologic factors known to influence prognosis.Conclusion: Five genetic markers were validated to be associated with lethal prostate cancer.Impact: This is the first population-based study to show that germline genetic variants provide prognostic information for prostate cancer-specific survival. The clinical utility of this five-SNP panel to stratify patients at higher risk for adverse outcomes should be evaluated. Cancer Epidemiol Biomarkers Prev; 20(9); 1928–36. ©2011 AACR.

PDF - 53K, Flow diagram of results from family- and bioinformatics-based filtering of whole-exome sequencing data and confirmation steps.

Summary 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 PC, 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., Genetic factors may distinguish who should receive active surveillance (AS) versus treatment following prostate cancer diagnosis. We undertook the first study to investigate this and report novel variants, genes, and risk scores associated with AS outcomes. These findings could help inform and individualize the decision of AS.

Background: Molecular studies have tried to address the unmet need for prognostic biomarkers in prostate cancer (PCa). Some gene expression tests improve upon clinical factors for prediction of outcomes, but additional tools for accurate prediction of tumor aggressiveness are needed. Methods: Based on a previously published panel of 23 gene transcripts that distinguished patients with metastatic progression, we constructed a prediction model using independent training and testing datasets. Using the validated messenger RNAs and Gleason score (GS), we performed model selection in the training set to define a final locked model to classify patients who developed metastatic-lethal events from those who remained recurrence-free. In an independent testing dataset, we compared our locked model to established clinical prognostic factors and utilized Kaplan-Meier curves and receiver operating characteristic analyses to evaluate the model's performance. Results: Thirteen of 23 previously identified gene transcripts that stratified patients with aggressive PCa were validated in the training dataset. These biomarkers plus GS were used to develop a four-gene (CST2, FBLN1, TNFRSF19, and ZNF704) transcript (4GT) score that was significantly higher in patients who progressed to metastatic-lethal events compared to those without recurrence in the testing dataset (P = 5.7 × 10-11). The 4GT score provided higher prediction accuracy (area under the ROC curve [AUC] = 0.76; 95% confidence interval [CI] = 0.69-0.83; partial area under the ROC curve [pAUC] = 0.008) than GS alone (AUC = 0.63; 95% CI = 0.56-0.70; pAUC = 0.002), and it improved risk stratification in subgroups defined by a combination of clinicopathological features (ie, Cancer of the Prostate Risk Assessment-Surgery). Conclusion: Our validated 4GT score has prognostic value for metastatic-lethal progression in men treated for localized PCa and warrants further evaluation for its clinical utility.

Background: There is preliminary evidence linking physical activity to better prostate cancer outcomes, though the molecular mechanisms underlying this association are not clear. Methods: In a Seattle-based cohort of patients diagnosed with clinically localized prostate cancer and prospective follow-up for outcomes (n = 1,354), we studied the association between self-reported vigorous physical activity and prostate cancer progression to a metastatic–lethal phenotype. A subset of patients had prostate cancer tissue samples available for investigating DNA methylation (Infinium HumanMethylation450 BeadChip array) and exercise (n = 524). Results: Patients who had vigorous physical activity at least once per week during the year before diagnosis (∼79% of the cohort) were significantly less likely to progress to metastatic–lethal prostate cancer compared with those who had vigorous physical activity less frequently (adjusted hazard ratio = 0.63; P = 0.029). Among the subset of men who had radical prostatectomy as primary treatment and tumor tissue available, a differentially methylated region (DMR) was identified (family-wise error rate = 0.03, hypomethylated in the weekly exercise group), with 9 methylation probes located in the promoter region of CRACR2A. This gene encodes a calcium binding protein involved in innate immune response. The methylation level of the nine CpGs was inversely correlated with CRACR2A gene expression (average correlation coefficient = –0.35). Conclusions: Vigorous physical activity before diagnosis is associated with epigenetic alterations of CRACR2A and prostate cancer metastatic–lethal progression. Impact: This analysis provides strong evidence for the association between vigorous physical activity and a less likelihood to develop metastatic–lethal progression, and a suggestive link between exercise and DNA methylation in the CRACRA2A gene.

This study examined whether differential DNA methylation is associated with clinical features of more aggressive disease at diagnosis and prostate cancer recurrence in African American men, who are more likely to die from prostate cancer than other populations. Tumor tissues from 76 African Americans diagnosed with prostate cancer who had radical prostatectomy as their primary treatment were profiled for epigenome-wide DNA methylation levels. Long-term follow-up identified 19 patients with prostate cancer recurrence. Twenty-three CpGs were differentially methylated (FDR q≤0.25, mean methylation difference ≥0.10) in patients with vs. without recurrence, including CpGs in GCK, CDKL2, PRDM13, and ZFR2. Methylation differences were also observed between men with metastatic-lethal prostate cancer vs. no recurrence (five CpGs), regional vs. local pathological stage (two CpGs), and higher vs. lower tumor aggressiveness (one CpG). These results indicate that differentially methylated CpG sites identified in tumor tissues of African American men may contribute to prostate cancer aggressiveness.

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.

Although many loci have been associated with height in European ancestry populations, very few have been identified in African ancestry individuals. Furthermore, many of the known loci have yet to be generalized to and fine-mapped within a large-scale African ancestry sample. We performed sex-combined and sex-stratified meta-analyses in up to 52,764 individuals with height and genome-wide genotyping data from the African Ancestry Anthropometry Genetics Consortium (AAAGC). We additionally combined our African ancestry meta-analysis results with published European genome-wide association study (GWAS) data. In the African ancestry analyses, we identified three novel loci (SLC4A3, NCOA2, ECD/FAM149B1) in sex-combined results and two loci (CRB1, KLF6) in women only. In the African plus European sex-combined GWAS, we identified an additional three novel loci (RCCD1, G6PC3, CEP95) which were equally driven by AAAGC and European results. Among 39 genome-wide significant signals at known loci, conditioning index SNPs from European studies identified 20 secondary signals. Two of the 20 new secondary signals and none of the 8 novel loci had minor allele frequencies (MAF) < 5%. Of 802 known European height signals, 643 displayed directionally consistent associations with height, of which 205 were nominally significant (p < 0.05) in the African ancestry sex-combined sample. Furthermore, 148 of 241 loci contained ≤20 variants in the credible sets that jointly account for 99% of the posterior probability of driving the associations. In summary, trans-ethnic meta-analyses revealed novel signals and further improved fine-mapping of putative causal variants in loci shared between African and European ancestry populations.

PURPOSE The 17-gene Onco type DX Genomic Prostate Score (GPS) test predicts adverse pathology (AP) in patients with low-risk prostate cancer treated with immediate surgery. We evaluated the GPS test as a predictor of outcomes in a multicenter active surveillance cohort. MATERIALS AND METHODS Diagnostic biopsy tissue was obtained from men enrolled at 8 sites in the Canary Prostate Active Surveillance Study. The primary endpoint was AP (Gleason Grade Group [GG] ≥ 3, ≥ pT3a) in men who underwent radical prostatectomy (RP) after initial surveillance. Multivariable regression models for interval-censored data were used to evaluate the association between AP and GPS. Inverse probability of censoring weighting was applied to adjust for informative censoring. Predictiveness curves were used to evaluate how models stratified risk of AP. Association between GPS and time to upgrade on surveillance biopsy was evaluated using Cox proportional hazards models. RESULTS GPS results were obtained for 432 men (median follow-up, 4.6 years); 101 underwent RP after a median 2.1 years of surveillance, and 52 had AP. A total of 167 men (39%) upgraded at a subsequent biopsy. GPS was significantly associated with AP when adjusted for diagnostic GG (hazards ratio [HR]/5 GPS units, 1.18; 95% CI, 1.04 to 1.44; P = .030), but not when also adjusted for prostate-specific antigen density (PSAD; HR, 1.85; 95% CI, 0.99 to 4.19; P = .066). Models containing PSAD and GG, or PSAD, GG, and GPS may stratify risk better than a model with GPS and GG. No association was observed between GPS and subsequent biopsy upgrade ( P = .48). CONCLUSION In our study, the independent association of GPS with AP after initial active surveillance was not statistically significant, and there was no association with upgrading in surveillance biopsy. Adding GPS to a model containing PSAD and diagnostic GG did not significantly improve stratification of risk for AP over the clinical variables alone.

Genome-wide association studies have identified more than 100 SNPs that increase the risk of prostate cancer (PrCa). We identify and compare expression quantitative trait loci (eQTLs) and CpG methylation quantitative trait loci (meQTLs) among 147 established PrCa risk SNPs in primary prostate tumors (n = 355 from a Seattle-based study and n = 495 from The Cancer Genome Atlas, TCGA) and tumor-adjacent, histologically benign samples (n = 471 from a Mayo Clinic study). The role of DNA methylation in eQTL regulation of gene expression was investigated by data triangulation using several causal inference approaches, including a proposed adaptation of the Causal Inference Test (CIT) for causal direction. Comparing eQTLs between tumors and benign samples, we show that 98 of the 147 risk SNPs were identified as eQTLs in the tumor-adjacent benign samples, and almost all 34 eQTL identified in tumor sets were also eQTLs in the benign samples. Three lines of results support the causal role of DNA methylation. First, nearly 100 of the 147 risk SNPs were identified as meQTLs in one tumor set, and almost all eQTLs in tumors were meQTLs. Second, the loss of eQTLs in tumors relative to benign samples was associated with altered DNA methylation. Third, among risk SNPs identified as both eQTLs and meQTLs, mediation analyses suggest that over two-thirds have evidence of a causal role for DNA methylation, mostly mediating genetic influence on gene expression. In summary, we provide a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PrCa risk SNPs. We observe that a substantial portion of germline eQTL regulatory mechanisms are maintained in the tumor development, despite somatic alterations in tumor genome. Finally, our mediation analyses illuminate the likely intermediary role of CpG methylation in eQTL regulation of gene expression., Author summary We conduct rigorous eQTL and meQTL mapping for the 147 confirmed PrCa risk SNPs using comprehensive genomic data in primary prostate tumors (TCGA and FHCRC) and tumor-adjacent benign samples (Mayo Clinic). The goal is to explore the biological mechanisms of how SNPs predispose to PrCa risk, and to investigate the causal role of DNA methylation in genetic regulation of gene expression. To our knowledge this is the first eQTL study for PrCa risk SNPs that includes the comparison between tumors and benign samples, as well as studying DNA methylation. We use several causal inference approaches, including a proposed adaptation of the Causal Inference Test (CIT) to decipher the direction of causality. We provide a comprehensive catalog of eQTLs, meQTLs and putative cancer genes for known PrCa risk SNPs, which shows eQTL regulatory mechanisms largely maintained in prostate tumors, and our mediation analyses shed light on the intermediary role of CpG methylation in eQTL regulation of gene expression.

BACKGROUNDS: Aside from Gleason score few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression. We hypothesized that copy number alterations (CNAs), assessed using CpG methylation probes on Illumina Infinium® Human Methylation450 (HM450K) BeadChip arrays, could identify primary prostate tumors with potential to develop metastatic progression. METHODS: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from two cohorts of PCa patients with clinically localized disease who underwent radical prostatectomy (RP) as primary therapy and were followed prospectively for at least five years: 1) a Fred Hutchinson (FH) Cancer Research Center-based cohort (n= 323 patients); and 2) an Eastern Virginia (EV) Medical School-based cohort (n= 78 patients). CNAs were identified using the R package ChAMP. Metastasis was confirmed by positive bone scan, MRI, CT or biopsy, and death certificates confirmed cause of death. RESULTS: We detected 15 recurrent CNAs were associated with metastasis in the FH cohort and replicated in the EV cohort (p< 0.05) without adjusting for Gleason score in the model. Eleven of the recurrent CNAs were associated with metastatic progression in the FH cohort and validated in the EV cohort (p

// Min A. Jhun 1 , Milan S. Geybels 1, 2 , Jonathan L. Wright 1, 3 , Suzanne Kolb 1 , Craig April 4 , Marina Bibikova 4 , Elaine A. Ostrander 5 , Jian-Bing Fan 4 , Ziding Feng 6 and Janet L. Stanford 1, 7 1 Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, USA 2 Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands 3 Department of Urology, University of Washington School of Medicine, Seattle, WA, USA 4 Department of Oncology, Illumina, Inc., San Diego, CA, USA 5 Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD, USA 6 Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX, USA 7 Department of Epidemiology, School of Public Health, University of Washington, Seattle, WA, USA Correspondence to: Janet L. Stanford, email: jstanfor@fredhutch.org Keywords: gene expression, Gleason score, prostate cancer, recurrence, metastasis Received: February 17, 2017 Accepted: March 30, 2017 Published: April 26, 2017 ABSTRACT Prostate cancer (PCa) is a leading cause of cancer-related mortality worldwide. Gleason score (GS) is one of the best predictors of PCa aggressiveness, but additional tumor biomarkers may improve its prognostic accuracy. We developed a gene expression signature of GS to enhance the prediction of PCa outcomes. Elastic net was used to construct a gene expression signature by contrasting GS 8-10 vs. ≤6 tumors in The Cancer Genome Atlas (TCGA) dataset. The constructed signature was then evaluated for its ability to predict recurrence and metastatic-lethal (ML) progression in a Fred Hutchinson (FH) patient cohort (N=408; N Recurrence =109; N MLprogression =27). The expression signature included transcripts representing 49 genes. In the FH cohort, a 25% increase in the signature was associated with a hazard ratio (HR) of 1.51 (P=2.7×10 −5 ) for recurrence. The signature’s area under the curve (AUC) for predicting recurrence and ML progression was 0.68 and 0.76, respectively. Compared to a model with age at diagnosis, pathological stage and GS, the gene expression signature improved the AUC for recurrence (3%) and ML progression (6%). Higher levels of the signature were associated with increased expression of genes in cell cycle-related pathways and decreased expression of genes in androgen response, estrogen response, oxidative phosphorylation, and apoptosis. This gene expression signature based on GS may improve the prediction of recurrence as well as ML progression in PCa patients after radical prostatectomy.

BACKGROUND DNA methylation has been hypothesized as a mechanism for explaining the association between smoking and adverse prostate cancer (PCa) outcomes. This study was aimed at assessing whether smoking is associated with prostate tumor DNA methylation and whether these alterations may explain in part the association of smoking with PCa recurrence and mortality. METHODS A total of 523 men had radical prostatectomy as their primary treatment, detailed smoking history data, long-term follow-up for PCa outcomes, and tumor tissue profiled for DNA methylation. Ninety percent of the men also had matched tumor gene expression data. A methylome-wide analysis was conducted to identify differentially methylated regions (DMRs) by smoking status. To select potential functionally relevant DMRs, their correlation with the messenger RNA (mRNA) expression of corresponding genes was evaluated. Finally, a smoking-related methylation score based on the top-ranked DMRs was created to assess its association with PCa outcomes. RESULTS Forty DMRs were associated with smoking status, and 10 of these were strongly correlated with mRNA expression (aldehyde oxidase 1 [AOX1], claudin 5 [CLDN5], early B-cell factor 1 [EBF1], homeobox A7 [HOXA7], lectin galactoside-binding soluble 3 [LGALS3], microtubule-associated protein τ [MAPT], protocadherin γ A [PCDHGA]/protocadherin γ B [PCDHGB], paraoxonase 3 [PON3], synaptonemal complex protein 2 like [SYCP2L], and zinc finger and SCAN domain containing 12 [ZSCAN12]). Men who were in the highest tertile for the smoking-methylation score derived from these DMRs had a higher risk of recurrence (odds ratio [OR], 2.29; 95% confidence interval [CI], 1.42-3.72) and lethal disease (OR, 4.21; 95% CI, 1.65-11.78) in comparison with men in the lower 2 tertiles. CONCLUSIONS This integrative molecular epidemiology study supports the hypothesis that smoking-associated tumor DNA methylation changes may explain at least part of the association between smoking and adverse PCa outcomes. Future studies are warranted to confirm these findings and understand the implications for improving patient outcomes. Cancer 2016;122:2168–77. © 2016 American Cancer Society.

BACKGROUND The epidemiologic evidence for an association of Trichomonas vaginalis (Tv) with overall prostate cancer is mixed, but some studies suggest Tv may increase risk of more aggressive disease. The aim of this study was to assess whether Tv serostatus is associated with advanced or fatal prostate cancer. METHODS A total of 146 men with advanced (metastatic or fatal) prostate cancer and 181 age-matched controls were selected from two prior population-based, case-control studies. Tv serostatus was determined with the same laboratory methods used in previous epidemiologic studies. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using multivariable logistic regression to compare Tv serostatus in prostate cancer cases and controls adjusted for potential confounders. RESULTS The seroprevalence of Tv in controls was 23%. Tv serostatus was not associated with an increased risk of metastatic or fatal prostate cancer (ORs

BACKGROUND Prognostic biomarkers for localized prostate cancer (PCa) could improve personalized medicine. Our group previously identified a panel of differentially methylated CpGs in primary tumor tissue that predict disease aggressiveness, and here we further validate these biomarkers. METHODS Pyrosequencing was used to assess CpG methylation of eight biomarkers previously identified using the HumanMethylation450 array; CpGs with strongly correlated (r >0.70) results were considered technically validated. Logistic regression incorporating the validated CpGs and Gleason sum was used to define and lock a final model to stratify men with metastatic-lethal versus non-recurrent PCa in a training dataset. Coefficients from the final model were then used to construct a DNA methylation score, which was evaluated by logistic regression and Receiver Operating Characteristic (ROC) curve analyses in an independent testing dataset. RESULTS Five CpGs were technically validated and all were retained (P

BACKGROUND: There is preliminary evidence linking physical activity to better prostate cancer (PCa) outcomes, though the molecular mechanisms underlying this association are not clear. METHODS: In a Seattle-based cohort of patients diagnosed with clinically localized PCa and prospective follow-up for outcomes (n=1354), we studied the association between self-reported vigorous physical activity and PCa progression to a metastatic-lethal phenotype. A subset of patients have prostate cancer tissue samples available for investigating DNA methylation (Infinium® HumanMethylation450 BeadChip array) and exercise (n=524). RESULTS: Patients who had vigorous physical activity at least once per week during the year before diagnosis (~79% of the cohort) were significantly less likely to progress to metastatic-lethal PCa compared to those who had vigorous physical activity less frequently (adjusted hazard ratio =0.63, p-value=0.029). Among the subset of men who had radical prostatectomy as primary treatment and tumor tissue available, a differentially methylated region (DMR) was identified (family-wise error rate=0.03, hypo-methylated in the weekly exercise group), with 9 methylation probes located in the promoter region of CRACR2A. This gene encodes a calcium binding protein involved in innate immune response. The methylation level of the nine CpGs was inversely correlated with CRACR2A gene expression (average correlation coefficient= – 0.35). CONCLUSIONS: Vigorous physical activity before diagnosis is associated with epigenetic alterations of CRACR2A and PCa metastatic lethal progression. IMPACT: This analysis provides strong evidence for the association between vigorous physical activity and a less likelihood to develop metastatic lethal progression, and a suggestive link between exercise and DNA methylation in CRACRA2A gene.

Background: Prostate cancer (PCa) is a leading cause of mortality and genetic factors can influence tumour aggressiveness. Several germline variants have been associated with PCa-specific mortality (PCSM), but further replication evidence is needed. Methods: Twenty-two previously identified PCSM-associated genetic variants were genotyped in seven PCa cohorts (12,082 patients; 1544 PCa deaths). For each cohort, Cox proportional hazards models were used to calculate hazard ratios and 95% confidence intervals for risk of PCSM associated with each variant. Data were then combined using a meta-analysis approach. Results Fifteen SNPs were associated with PCSM in at least one of the seven cohorts. In the meta-analysis, after adjustment for clinicopathological factors, variants in the MGMT (rs2308327; HR 0.90; p-value = 3.5 x 10(-2)) and IL4 (rs2070874; HR 1.22; p-value = 1.1 x 10(-3)) genes were confirmed to be associated with risk of PCSM. In analyses limited to men diagnosed with local or regional stage disease, a variant in AKT1, rs2494750, was also confirmed to be associated with PCSM risk (HR 0.81; p-value = 3.6 x 10(-2)). Conclusions: This meta-analysis confirms the association of three genetic variants with risk of PCSM, providing further evidence that genetic background plays a role in PCa-specific survival. While these variants alone are not sufficient as prognostic biomarkers, these results may provide insights into the biological pathways modulating tumour aggressiveness.

BACKGROUND Prostate cancer (PCa) is clinically and biologically heterogeneous, making it difficult to predict at detection whether it will take an indolent or aggressive disease course. Cell cycle-regulated genes may be more highly expressed in actively dividing cells, with transcript levels reflecting tumor growth rate. Here, we evaluated expression of cell cycle genes in relation to PCa outcomes in a population-based cohort. METHODS Gene expression data were generated from tumor tissues obtained at radical prostatectomy for 383 population-based patients (12.3-years average follow-up). The overall mean and individual transcript levels of 30 selected cell cycle genes was compared between patients with no evidence of recurrence (73%) and those who recurred (27%) or died (7%) from PCa. RESULTS The multivariate adjusted hazard ratio (HR) for a change from the 25th to 75th percentile of mean gene expression level (range 8.02–10.05) was 1.25 (95%CI 0.96–1.63; P = 0.10) for PCa recurrence risk, and did not vary substantially by Gleason score, TMPRSS2-ERG fusion status, or family history of PCa. For lethal PCa, the HR for a change (25th to 75th percentile) in mean gene expression level was 2.04 (95%CI 1.26–3.31; P = 0.004), adjusted for clinicopathological variables. The ROC curve for mean gene expression level alone (AUC = 0.740) did not perform as well as clinicopathological variables alone (AUC = 0.803) for predicting lethal PCa, and the addition of mean gene expression to clinicopathological variables did not substantially improve prediction (AUC = 0.827; P = 0.18). Higher TK1 expression was strongly associated with both recurrent (P = 6.7 × 10−5) and lethal (P = 6.4 × 10−6) PCa. CONCLUSIONS Mean expression level for 30 selected cell cycle-regulated genes was unrelated to recurrence risk, but was associated with a twofold increase in risk of lethal PCa. However, gene expression had less discriminatory accuracy than clinical variables alone for predicting lethal events. Transcript levels for several genes in the panel were significantly overexpressed in lethal versus non-recurrent PCa. Prostate 75:1354–1362, 2015. © 2015 Wiley Periodicals, Inc.

The T2E gene fusion, formed by fusion of the transmembrane protease, serine 2, gene (TMPRSS2) with the erythroblast transformation-specific (ETS)-related gene (ERG), is found in approximately 50% of prostate cancers and may characterize distinct molecular subtypes of prostate cancer with different etiologies. We investigated the relationship between body mass index (BMI; weight (kg)/height (m)(2)) and prostate cancer risk by T2E status. Study participants were residents of King County, Washington, recruited for 2 population-based case-control studies conducted in 1993-1996 and 2002-2005. Tumor T2E status was determined for 563 prostate cancer patients who underwent radical prostatectomy. Information on weight, height, and covariables was obtained through in-person interviews. We performed polytomous logistic regression to calculate odds ratios and 95% confidence intervals for T2E-positive and -negative prostate cancer. Comparing the highest BMI quartile with the lowest, inverse associations were observed between recent (≥29.7 vs.

Purpose: Aside from Gleason sum, few factors accurately identify the subset of prostate cancer patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Experimental Design: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of prostate cancer patients followed prospectively for at least 5 years. Metastasis was confirmed by positive bone scan, MRI, CT, or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from nonrecurrent tumors, and which were complementary to Gleason sum. Results: Forty-two CpG biomarkers stratified patients with metastatic-lethal versus nonrecurrent prostate cancer in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P < 0.05) AUC (range, 0.66–0.75) or pAUC (range, 0.007–0.009). The biomarkers that improved discrimination of patients with metastatic-lethal prostate cancer include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset, the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range, 0.86–0.89; all P Conclusions: Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from nonrecurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized prostate cancer and provide new insights on tumor aggressiveness. Clin Cancer Res; 23(1); 311–9. ©2016 AACR.

Genome-wide association studies have identified more than 80 risk variants for prostate cancer, mainly in European or Asian populations. The generalizability of these variants in other racial/ethnic populations needs to be understood before the loci can be used widely in risk modeling. In our study, we examined 82 previously reported risk variants in 4,853 prostate cancer cases and 4,678 controls of African ancestry. We performed association testing for each variant using logistic regression adjusted for age, study and global ancestry. Of the 82 known risk variants, 68 (83%) had effects that were directionally consistent in their association with prostate cancer risk and 30 (37%) were significantly associated with risk at p < 0.05, with the most statistically significant variants being rs116041037 (p = 3.7 × 10(-26) ) and rs6983561 (p = 1.1 × 10(-16) ) at 8q24, as well as rs7210100 (p = 5.4 × 10(-8) ) at 17q21. By exploring each locus in search of better markers, the number of variants that captured risk in men of African ancestry (p < 0.05) increased from 30 (37%) to 44 (54%). An aggregate score comprised of these 44 markers was strongly associated with prostate cancer risk [per-allele odds ratio (OR) = 1.12, p = 7.3 × 10(-98) ]. In summary, the consistent directions of effects for the vast majority of variants in men of African ancestry indicate common functional alleles that are shared across populations. Further exploration of these susceptibility loci is needed to identify the underlying biologically relevant variants to improve prostate cancer risk modeling in populations of African ancestry.

Background: One challenge in prostate cancer is distinguishing indolent from aggressive disease at diagnosis. DNA promoter hypermethylation is a frequent epigenetic event in prostate cancer, but few studies of DNA methylation in relation to features of more aggressive tumors or prostate cancer recurrence have been completed. Methods: We used the Infinium HumanMethylation450 BeadChip to assess DNA methylation in tumor tissue from 407 patients with clinically localized prostate cancer who underwent radical prostatectomy. Recurrence status was determined by follow-up patient surveys, medical record review, and linkage with the Surveillance, Epidemiology, and End Results (SEER) registry. The methylation status of 14 genes for which promoter hypermethylation was previously correlated with advanced disease or biochemical recurrence was evaluated. Average methylation level for promoter region CpGs in patients who recurred compared with those with no evidence of recurrence was analyzed. For two genes with differential methylation, time to recurrence was examined. Results: During an average follow-up of 11.7 years, 104 (26%) patients recurred. Significant promoter hypermethylation in at least 50% of CpG sites in two genes, ABHD9 and HOXD3, was found in tumors from patients who recurred compared with those without recurrence. Evidence was strongest for HOXD3 (lowest P = 9.46 × 10−6), with higher average methylation across promoter region CpGs associated with reduced recurrence-free survival (P = 2 × 10−4). DNA methylation profiles did not differ by recurrence status for the other genes. Conclusions: These results validate the association between promoter hypermethylation of ADHB9 and HOXD3 and prostate cancer recurrence. Impact: Tumor DNA methylation profiling may help to distinguish patients with prostate cancer at higher risk for disease recurrence. Cancer Epidemiol Biomarkers Prev; 23(7); 1331–9. ©2014 AACR.

Genome-wide association studies (GWAS) have identified 76 variants associated with prostate cancer risk predominantly in populations of European ancestry. To identify additional susceptibility loci for this common cancer, we conducted a meta-analysis of > 10 million SNPs in 43,303 prostate cancer cases and 43,737 controls from studies in populations of European, African, Japanese and Latino ancestry. Twenty-three new susceptibility loci were identified at association P < 5 × 10(-8); 15 variants were identified among men of European ancestry, 7 were identified in multi-ancestry analyses and 1 was associated with early-onset prostate cancer. These 23 variants, in combination with known prostate cancer risk variants, explain 33% of the familial risk for this disease in European-ancestry populations. These findings provide new regions for investigation into the pathogenesis of prostate cancer and demonstrate the usefulness of combining ancestrally diverse populations to discover risk loci for disease.

Background: Rare, inherited mutations account for 5% to 10% of all prostate cancer cases. However, to date, few causative mutations have been identified. Methods: To identify rare mutations for prostate cancer, we conducted whole-exome sequencing (WES) in multiple kindreds (n = 91) from 19 hereditary prostate cancer (HPC) families characterized by aggressive or early-onset phenotypes. Candidate variants (n = 130) identified through family- and bioinformatics-based filtering of WES data were then genotyped in an independent set of 270 HPC families (n = 819 prostate cancer cases; n = 496 unaffected relatives) for replication. Two variants with supportive evidence were subsequently genotyped in a population-based case–control study (n = 1,155 incident prostate cancer cases; n = 1,060 age-matched controls) for further confirmation. All participants were men of European ancestry. Results: The strongest evidence was for two germline missense variants in the butyrophilin-like 2 (BTNL2) gene (rs41441651, p.Asp336Asn and rs28362675, p.Gly454Cys) that segregated with affection status in two of the WES families. In the independent set of 270 HPC families, 1.5% (rs41441651; P = 0.0032) and 1.2% (rs28362675; P = 0.0070) of affected men, but no unaffected men, carried a variant. Both variants were associated with elevated prostate cancer risk in the population-based study (rs41441651: OR, 2.7; 95% CI, 1.27–5.87; P = 0.010; rs28362675: OR, 2.5; 95% CI, 1.16–5.46; P = 0.019). Conclusions: Results indicate that rare BTNL2 variants play a role in susceptibility to both familial and sporadic prostate cancer. Impact: Results implicate BTNL2 as a novel prostate cancer susceptibility gene. Cancer Epidemiol Biomarkers Prev; 22(9); 1520–8. ©2013 AACR.

Background—We investigated associations between statin use begun before PCa diagnosis and prostate cancer (PCa) recurrence/progression and PCa-specific mortality (PCSM) in a prospective, population-based cohort study. Methods—The analysis included 1,001 PCa patients diagnosed in 2002–2005 in King County, Washington. Statin use was assessed at baseline using a detailed in-person interview. Prostate cancer recurrence/progression events and cause-specific survival were ascertained from a followup survey and the SEER registry. Multivariable competing risk and Cox proportional hazards regression models were used to assess the risk of PCa outcomes according to categories of statin use. Results—Of the 1,001 PCa patients in our study, 289 men were ever users of statin drugs. During follow-up, we identified 151 PCa recurrence/progression events and 123 total deaths, including 39 PCa-specific deaths. In unadjusted analysis, the risk of PCa-specific mortality (PCSM) was significantly lower for statin users compared to non-users (1% versus 5% at 10 years; P

Genome-wide association studies (GWAS) have identified 36 loci associated with body mass index (BMI), predominantly in populations of European ancestry. We conducted a meta-analysis to examine the association of3.2 million SNPs with BMI in 39,144 men and women of African ancestry and followed up the most significant associations in an additional 32,268 individuals of African ancestry. We identified one new locus at 5q33 (GALNT10, rs7708584, P = 3.4 × 10(-11)) and another at 7p15 when we included data from the GIANT consortium (MIR148A-NFE2L3, rs10261878, P = 1.2 × 10(-10)). We also found suggestive evidence of an association at a third locus at 6q16 in the African-ancestry sample (KLHL32, rs974417, P = 6.9 × 10(-8)). Thirty-two of the 36 previously established BMI variants showed directionally consistent effect estimates in our GWAS (binomial P = 9.7 × 10(-7)), five of which reached genome-wide significance. These findings provide strong support for shared BMI loci across populations, as well as for the utility of studying ancestrally diverse populations.

Prostate cancer (PCa) susceptibility is defined by a continuum from rare, high-penetrance to common, low-penetrance alleles. Research to date has concentrated on identification of variants at the ends of that continuum. Taking an alternate approach, we focused on the important but elusive class of low-frequency, moderately penetrant variants by performing disease model-based variant filtering of whole exome sequence data from 75 hereditary PCa families. Analysis of 341 candidate risk variants identified nine variants significantly associated with increased PCa risk in a population-based, case-control study of 2,495 men. In an independent nested case-control study of 7,121 men, there was risk association evidence for TANGO2 p.Ser17Ter and the established HOXB13 p.Gly84Glu variant. Meta-analysis combining the case-control studies identified two additional variants suggestively associated with risk, OR5H14 p.Met59Val and CHAD p.Ala342Asp. The TANGO2 and HOXB13 variants co-occurred in cases more often than expected by chance and never in controls. Finally, TANGO2 p.Ser17Ter was associated with aggressive disease in both case-control studies separately. Our analyses identified three new PCa susceptibility alleles in the TANGO2, OR5H14 and CHAD genes that not only segregate in multiple high-risk families but are also of importance in altering disease risk for men from the general population. This is the first successful study to utilize sequencing in high-risk families for the express purpose of identifying low-frequency, moderately penetrant PCa risk mutations.

Prognostic biomarkers are needed to distinguish patients with clinically localized prostate cancer (PCa) who are at high risk of metastatic progression. The tumor transcriptome may reveal its aggressiveness potential and have utility for predicting adverse patient outcomes. Genomewide gene expression levels were measured in primary tumor samples of 383 patients in a population-based discovery cohort, and from an independent clinical validation dataset of 78 patients. Patients were followed for >= 5 years after radical prostatectomy to ascertain outcomes. Area under the receiver- operating characteristic curve (AUC), partial AUC (pAUC, 95% specificity), and P- value criteria were used to detect and validate the differentially expressed transcripts. Twenty-three differentially expressed transcripts in patients with metastatic-lethal compared with nonrecurrent PCa were validated (P

Prostate cancer is the most frequently diagnosed cancer in males in developed countries. To identify common prostate cancer susceptibility alleles, we genotyped 211,155 SNPs on a custom Illumina array (iCOGS) in blood DNA from 25,074 prostate cancer cases and 24,272 controls from the international PRACTICAL Consortium. Twenty-three new prostate cancer susceptibility loci were identified at genome-wide significance (P < 5 × 10(-8)). More than 70 prostate cancer susceptibility loci, explaining ∼30% of the familial risk for this disease, have now been identified. On the basis of combined risks conferred by the new and previously known risk loci, the top 1% of the risk distribution has a 4.7-fold higher risk than the average of the population being profiled. These results will facilitate population risk stratification for clinical studies.

The 8q24 region harbors multiple risk variants for distinct cancers, including >8 for prostate cancer. In this study, we conducted fine mapping of the 8q24 risk region (127.8-128.8Mb) in search of novel associations with common and rare variation in 4853 prostate cancer case patients and 4678 control subjects of African ancestry. All statistical tests were two-sided. We identified three independent associations at P values of less than 5.00×10(-8), all of which were replicated in studies from Ghana and Uganda (combined sample = 5869 case patients, 5615 control subjects; rs114798100: risk allele frequency [RAF] = 0.04, per-allele odds ratio [OR] = 2.31, 95% confidence interval [CI] = 2.04 to 2.61, P = 2.38×10(-40); rs72725879: RAF = 0.33, OR = 1.37, 95% CI = 1.30 to 1.45, P = 3.04×10(-27); and rs111906932: RAF = 0.03, OR = 1.79, 95% CI = 1.53 to 2.08, P = 1.39×10(-13)). Risk variants rs114798100 and rs111906923 are only found in men of African ancestry, with rs111906923 representing a novel association signal. The three variants are located within or near a number of prostate cancer-associated long noncoding RNAs (lncRNAs), including PRNCR1, PCAT1, and PCAT2. These findings highlight ancestry-specific risk variation and implicate prostate-specific lncRNAs at the 8q24 prostate cancer susceptibility region.

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.

Two genome-wide association studies (GWAS) identified the β-microseminoprotein (MSMB) promoter SNP, rs10993994:C>T, as significantly associated with prostate cancer (PC) risk. Follow-up studies demonstrate that the variant allele directly affects expression of the MSMB-encoded protein, PSP94, and also suggest that it affects mRNA expression levels of an adjacent gene, NCOA4, which is involved in androgen receptor transactivation. In a population-based study of 1,323 cases and 1,268 age-matched controls, we found the NCOA4 SNP, rs7350420:T>C, was associated with a 15% reduction in PC risk, but the association was not significant after adjustment for the rs10993994:C>T genotype. Tumor tissue microarrays of 519 radical prostatectomy patients were used to measure PSP94 and NCOA4 protein expression. Taken together, these data confirm that the rs10993994:C>T variant allele is associated with decreased PSP94 expression, and the association is stronger in tumor compared to normal prostate tissue. No association was observed between rs10993994:C>T and NCOA4 expression, and only moderate associations were seen between two NCOA4 SNPs, rs10761618:T>C and rs7085433:G>A, and NCOA4 protein expression. These data indicate that the increase in PC risk associated with rs10993994:C>T is likely mediated by the variant's effect on PSP94 expression; however, this effect does not extend to NCOA4 in the data presented here.

BACKGROUND Through mediation of estrogen receptors, estradiol has been shown to have both carcinogenic and anti-carcinogenic effects on the prostate. We performed a population-based case–control study to investigate variants in estrogen-related genes ESR1, ESR2, CYP19A1, CYP1A1, and CYP1B1 and the potential association with risk of prostate cancer (PCa). MATERIALS AND METHODS We evaluated PCa risk conferred by 73 single nucleotide polymorphisms in 1,304 incident PCa cases and 1,266 age-matched controls. Analysis included stratification by clinical features and assessment of environmental modifiers. RESULTS There was evidence of altered risk of developing PCa for variants in ESR1, CYP1A1, and CYP1B1, however, only CYP1B1 rs1056836 retained significance after adjustment for multiple comparisons. An association with risk for more aggressive PCa was observed for variants in ESR1, ESR2, and CYP19A1, but none was significant after adjustment for multiple comparisons. There was no effect modification by obesity. CONCLUSIONS Germline genetic variation of these estrogen pathway genes may contribute to risk of PCa. Additional studies to validate these results and examine the functional consequence of validated variants are warranted. Prostate 73: 1–10, 2013. © 2012 Wiley Periodicals, Inc.