Association of germline rare pathogenic mutations in guideline-recommended genes with prostate cancer progression: A meta-analysis.

BACKGROUND: Germline mutations in several genes, mainly DNA repair genes, have been associated with prostate cancer (PCa) progression. However, primarily due to the rarity of mutations, statistical evidence for these associations is not consistently established. The objective of this study is to synthesize evidence from multiple studies using a meta-analysis. METHODS: Genes analyzed were chosen based on National Comprehensive Cancer Network guidelines recommendations (10 genes) and a commonly reported gene (NBN). PCa progression in this analysis was defined as either having metastases or PCa-specific mortality. We searched PubMed for papers published before April 26, 2021, using selected keywords. Pooled odds ratio (OR) was estimated in all races and Caucasians-only using both fixed- and random-effect models. RESULTS: The search identified 1028 papers and an additional five from a manual review of references. After a manual process that excluded noneligible studies, 11 papers remained, including a total of 3944 progressors and 20,054 nonprogressors. Combining results from these eligible studies, mutation carrier rates were significantly higher in progressors than nonprogressors for NBN, BRCA2, ATM (under both fixed- and random-effect models), for CHEK2 (under fixed-effect model only), and for PALB2 (under random-effect model only), p < 0.05. Pooled OR (95% confidence interval) was 6.38 (2.25-18.05), 3.41 (2.31; 5.03), 1.93 (1.17-3.20), and 1.53 (1.00-2.33) for NBN, BRCA2, ATM, and CHEK2, respectively, under fixed-effect model and 2.63 (1.12-6.13) for PALB2 under random-effect model. No significant association was found for the six remaining genes. Certainty of evidence was low for many genes due primarily to the limited number of eligible studies and mutation carriers. CONCLUSIONS: Statistical evidence for five genes was obtained in this first meta-analysis of germline mutations and PCa progression. While these results may help urologists and genetic counselors interpret germline testing results for PCa progression, more original studies are needed.

Assessing the clinical utility of genetic risk scores for targeted cancer screening.

BACKGROUND: Genome-wide association studies have identified thousands of disease-associated single nucleotide polymorphisms (SNPs). A subset of these SNPs may be additively combined to generate genetic risk scores (GRSs) that confer risk for a specific disease. Although the clinical validity of GRSs to predict risk of specific diseases has been well established, there is still a great need to determine their clinical utility by applying GRSs in primary care for cancer risk assessment and targeted intervention. METHODS: This clinical study involved 281 primary care patients without a personal history of breast, prostate or colorectal cancer who were 40-70 years old. DNA was obtained from a pre-existing biobank at NorthShore University HealthSystem. GRSs for colorectal cancer and breast or prostate cancer were calculated and shared with participants through their primary care provider. Additional data was gathered using questionnaires as well as electronic medical record information. A t-test or Chi-square test was applied for comparison of demographic and key clinical variables among different groups. RESULTS: The median age of the 281 participants was 58 years and the majority were female (66.6%). One hundred one (36.9%) participants received 2 low risk scores, 99 (35.2%) received 1 low risk and 1 average risk score, 37 (13.2%) received 1 low risk and 1 high risk score, 23 (8.2%) received 2 average risk scores, 21 (7.5%) received 1 average risk and 1 high risk score, and no one received 2 high risk scores. Before receiving GRSs, younger patients and women reported significantly more worry about risk of developing cancer. After receiving GRSs, those who received at least one high GRS reported significantly more worry about developing cancer. There were no significant differences found between gender, age, or GRS with regards to participants' reported optimism about their future health neither before nor after receiving GRS results. CONCLUSIONS: Genetic risk scores that quantify an individual's risk of developing breast, prostate and colorectal cancers as compared with a race-defined population average risk have potential clinical utility as a tool for risk stratification and to guide cancer screening in a primary care setting.

Validation of a prostate cancer polygenic risk score.

BACKGROUND: Genome-wide association studies have identified over 100 single-nucleotide polymorphisms (SNPs) associated with prostate cancer (PrCa), and polygenic risk scores (PRS) based on their combined genotypes have been developed for risk stratification. We aimed to assess the contribution of PRS to PrCa risk in a large multisite study. METHODS: The sample included 1972 PrCa cases and 1919 unaffected controls. Next-generation sequencing was used to assess pathogenic variants in 14 PrCa-susceptibility genes and 72 validated PrCa-associated SNPs. We constructed a population-standardized PRS and tested its association with PrCa using logistic regression adjusted for age and family history of PrCa. RESULTS: The mean age of PrCa cases at diagnosis and age of controls at testing/last clinic visit was 59.5 ± 7.2 and 57.2 ± 13.0 years, respectively. Among 1740 cases with pathology data, 57.4% had Gleason score ≤ 6, while 42.6% had Gleason score ≥ 8. In addition, 39.6% cases and 20.1% controls had a family history of PrCa. The PRS was significantly higher in cases than controls (mean ± SD: 1.42 ± 1.11 vs 1.02 ± 0.76; P < .0001). Compared with men in the 1st quartile of age-adjusted PRS, those in the 2nd, 3rd, and 4th quartile were 1.58 (95% confidence interval [CI]: 1.31-1.90), 2.36 (95% CI: 1.96-2.84), and 3.98 (95% CI: 3.29-4.82) times as likely to have PrCa (all P < .0001). Adjustment for family history yielded similar results. PRS predictive performance was consistent with prior literature (area under the receiver operating curve = 0.64; 95% CI: 0.62-0.66). CONCLUSIONS: These data suggest that a 72-SNP PRS is predictive of PrCa, supporting its potential use in clinical risk assessment.

Germline mutations in PPFIBP2 are associated with lethal prostate cancer.

BACKGROUND: Few genes have germline mutations which predispose men to more aggressive prostate cancer (PCa). This study evaluated the contribution of germline loss of function (LOF) variants in PPFIBP2 to risk of lethal PCa. METHODS: A case-case study of 1414 PCa patients with lethal PCa and low-risk localized PCa was performed. Germline DNA samples from these patients were sequenced for PPFIBP2. Mutation carrier rates and association with lethal PCa were analyzed using the Fisher exact test, logistic regression, and Kaplan-Meier survival analysis. RESULTS: In the entire study population, eight patients, all of European ancestry, were identified as carrying PPFIBP2 pathogenic or likely pathogenic mutations. Seven (1.52%) of 462 lethal PCa patients were carriers compared with only one (0.12%) carrier in 810 low-risk PCa patients, P = 0.0029. The estimated Odds Ratio (OR) of carrying PPFIBP2 mutation for lethal PCa was 13.8 in European American population. The PPFIBP2 loss-of-function mutation carrier rate in lethal PCa cases was also higher than in 33 370 non-Finnish European individuals from the Exome Aggregation Consortium (ExAC) (carrier rate of 0.17%, P = 1.92 × 10-5 ) and in 498 men with localized PCa from The Cancer Genome Atlas cohort (TCGA) cohort (carrier rate of 0%, P = 0.0058). Survival analysis in European American lethal cases revealed PPFIBP2 mutation status as an independent predictor of shorter survival after adjusting for age at diagnosis, PSA at diagnosis, and genetic background (hazard ratio = 2.62, P = 0.034). CONCLUSIONS: While larger studies are needed, germline mutations in a novel gene, PPFIBP2, differentiated risk for lethal PCa from low-risk cases and were associated with shorter survival times after diagnosis.

TEX15: A DNA repair gene associated with prostate cancer risk in Han Chinese.

BACKGROUND: Both common and rare genetic variants may contribute to risk of developing prostate cancer. Genome-wide association studies (GWASs) have identified ∼100 independent, common variants associated with prostate cancer risk. However, little is known about the association of rare variants (minor allele frequency [MAF] <1%) in the genome with prostate cancer risk. METHODS: A two-stage study was used to test the association of rare, deleterious coding variants, annotated using predictive algorithms, with prostate cancer risk in Chinese men. Predicted rare, deleterious coding variants in the Illumina HumanExome-12 v1.1 beadchip were first evaluated in 1343 prostate cancer patients and 1008 controls. Significant variants were then validated in an additional 1816 prostate cancer patients and 1549 controls. RESULTS: In the discovery stage, 14 predicted rare, deleterious coding variants were significantly associated with prostate cancer risk (P < 0.01). In the confirmation stage, Q1631H in TEX15 (rs142485241), a DNA repair gene, was significantly associated with prostate cancer risk (P = 0.0069). The estimated odds ratio (OR) of the variant in the combined analysis was 3.24 (95% Confidence Interval 1.85-6.06), P = 8.81 × 10-5 . Additionally, rs28756990 (V741F) at MLH3 (P = 0.06) and rs2961144 (I126V) at OR2A5 (P = 0.065) were marginally associated with prostate cancer risk in the replication stage. CONCLUSIONS: Our study provided preliminary evidence that the rare variant Q1631H in DNA repair gene TEX15 is associated with prostate cancer risk. This finding complements known common prostate cancer risk-associated variants and suggests the possible role of DNA repair genes in prostate cancer development.

Inherited genetic variant predisposes to aggressive but not indolent prostate cancer.

Autopsy studies suggest that most aging men will develop lesions that, if detected clinically, would be diagnosed as prostate cancer (PCa). Most of these cancers are indolent and remain localized; however, a subset of PCa is aggressive and accounts for more than 27,000 deaths in the United States annually. Identification of factors specifically associated with risk for more aggressive PCa is urgently needed to reduce overdiagnosis and overtreatment of this common disease. To search for such factors, we compared the frequencies of SNPs among PCa patients who were defined as having either more aggressive or less aggressive disease in four populations examined in the Genetic Markers of Susceptibility (CGEMS) study performed by the National Cancer Institute. SNPs showing possible associations with disease severity were further evaluated in an additional three independent study populations from the United States and Sweden. In total, we studied 4,829 and 12,205 patients with more and less aggressive disease, respectively. We found that the frequency of the TT genotype of SNP rs4054823 at 17p12 was consistently higher among patients with more aggressive compared with less aggressive disease in each of the seven populations studied, with an overall P value of 2.1 x 10(-8) under a recessive model, exceeding the conservative genome-wide significance level. The difference in frequency was largest between patients with high-grade, non-organ-confined disease compared with those with low-grade, organ-confined disease. This study demonstrates that inherited variants predisposing to aggressive but not indolent PCa exist in the genome, and suggests that the clinical potential of such variants as potential early markers for risk of aggressive PCa should be evaluated.

Association of Reported Candidate Monogenic Genes With Lung Cancer Risk.

INTRODUCTION/BACKGROUND: Published studies on association of germline monogenic genes and lung cancer risk were inconsistent. Our objective is to assess the validity of reported candidate monogenic genes for their association with lung cancer. MATERIALS AND METHODS: A systematic review of published papers prior to August 2022 was performed first to identify all genes where germline mutations were associated with lung cancer risk. We then performed a confirmation study in 2,050 lung cancer cases and 198,553 controls in the UK Biobank (UKB). Germline mutations of these genes were identified from sequencing data and annotated using The American College of Medical Genetics criteria. The robust SKAT-O, a gene-based analysis that properly controls for false positives due to unbalanced case-control ratio, was used for association tests adjusting for age at recruitment, gender, and genetic background. RESULTS: The systematic review identified 12 genes that were statistically significantly associated with lung cancer risk in at least one study (P < .05), including ATM, BLM, BRCA2, BRIP1, CHEK2, FANCA, FANCD2, MSH6, PMS1, RAD51C, RAD51D, and TP53. When pathogenic/likely pathogenic mutations were aggregated within each gene, the association was confirmed for ATM (P = 4.47E-4) at the study-wise significance level (P < .0042, Bonferroni correction for 12 tests). Suggestive evidence of association was found for 2 other genes, BRCA2 (P = .007) and TP53 (P = .03). Among these 3 genes, the lung cancer risks range from 1.95 (BRCA2) to 5.28 (TP53). CONCLUSION: This study provides statistical evidence for association of previously reported genes and lung cancer risk and has clinical utility for risk assessment and genetic counseling.

Risk assessment of venous thromboembolism in inflammatory bowel disease by inherited risk in a population-based incident cohort.

BACKGROUND: Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disease of the digestive tract with increasing prevalence globally. Although venous thromboembolism (VTE) is a major complication in IBD patients, it is often underappreciated with limited tools for risk stratification. AIM: To estimate the proportion of VTE among IBD patients and assess genetic risk factors (monogenic and polygenic) for VTE. METHODS: Incident VTE was followed for 8465 IBD patients in the UK Biobank (UKB). The associations of VTE with F5 factor V leiden (FVL) mutation, F2 G20210A prothrombin gene mutation (PGM), and polygenic score (PGS003332) were tested using Cox hazards regression analysis, adjusting for age at IBD diagnosis, gender, and genetic background (top 10 principal components). The performance of genetic risk factors for discriminating VTE diagnosis was estimated using the area under the receiver operating characteristic curve (AUC). RESULTS: The overall proportion of incident VTE was 4.70% in IBD patients and was similar for CD (4.46%), UC (4.49%), and unclassified (6.42%), and comparable to that of cancer patients (4.66%) who are well-known at increased risk for VTE. Mutation carriers of F5/F2 had a significantly increased risk for VTE compared to non-mutation carriers, hazard ratio (HR) was 1.94, 95% confidence interval (CI): 1.42-2.65. In contrast, patients with the top PGS decile had a considerably higher risk for VTE compared to those with intermediate scores (middle 8 deciles), HR was 2.06 (95%CI: 1.57-2.71). The AUC for differentiating VTE diagnosis was 0.64 (95%CI: 0.61-0.67), 0.68 (95%CI: 0.66-0.71), and 0.69 (95%CI: 0.66-0.71), respectively, for F5/F2 mutation carriers, PGS, and combined. CONCLUSION: Similar to cancer patients, VTE complications are common in IBD patients. PGS provides more informative risk information than F5/F2 mutations (FVL and PGM) for personalized thromboprophylaxis.

Human polymorphisms at long non-coding RNAs (lncRNAs) and association with prostate cancer risk.

Long non-coding RNAs (lncRNAs), representing a large proportion of non-coding transcripts across the human genome, are evolutionally conserved and biologically functional. At least one-third of the phenotype-related loci identified by genome-wide association studies (GWAS) are mapped to non-coding intervals. However, the relationships between phenotype-related loci and lncRNAs are largely unknown. Utilizing the 1000 Genomes data, we compared single-nucleotide polymorphisms (SNPs) within the sequences of lncRNA and protein-coding genes as defined in the Ensembl database. We further annotated the phenotype-related SNPs reported by GWAS at lncRNA intervals. Because prostate cancer (PCa) risk-related loci were enriched in lncRNAs, we then performed meta-analysis of two existing GWAS for discovery and an additional sample set for replication, revealing PCa risk-related loci at lncRNA regions. The SNP density in regions of lncRNA was similar to that in protein-coding regions, but they were less polymorphic than surrounding regions. Among the 1998 phenotype-related SNPs identified by GWAS, 52 loci were located directly in lncRNA intervals with a 1.5-fold enrichment compared with the entire genome. More than a 5-fold enrichment was observed for eight PCa risk-related loci in lncRNA genes. We also identified a new PCa risk-related SNP rs3787016 in an lncRNA region at 19q13 (per allele odds ratio = 1.19; 95% confidence interval: 1.11-1.27) with P value of 7.22 × 10(-7). lncRNAs may be important for interpreting and mining GWAS data. However, the catalog of lncRNAs needs to be better characterized in order to fully evaluate the relationship of phenotype-related loci with lncRNAs.

Association of 17 prostate cancer susceptibility loci with prostate cancer risk in Chinese men.

BACKGROUND: Several genome-wide association studies (GWAS) in populations of European descent have identified more than a dozen common genetic variants that are associated with prostate cancer risk. METHODS: To determine whether these variants are also associated with prostate cancer risk in the Chinese population, we evaluated 17 prostate cancer susceptibility loci in a population-based case-control study from Shanghai, including 288 prostate cancer cases and 155 population controls. RESULTS: After adjustment for age, two of the 17 loci were significantly associated with prostate cancer risk, while the other 15 loci were suggestively associated with prostate cancer risk in this population. The strongest associations were found for chromosome 8q24 Region 2 (rs1016343: OR = 2.07, 95% CI: 1.35-3.20, P = 9.4 x 10(-4)) and 8q24 Region 1 (rs10090154: OR = 2.07, 95% CI: 1.31-3.28, P = 0.002); additional single nucleotide polymorphisms (SNPs) assessed in these two 8q24 regions were also significant (OR(Region2) = 1.92-2.05, P = 9.4 x 10(-4) to 0.003, and OR(Region1) = 1.77-1.81, P = 0.01 for all SNPs). CONCLUSIONS: Our study shows that multiple prostate cancer risk loci identified in European populations by GWAS are also associated with prostate cancer risk in Chinese men, a low-risk population with mostly clinically relevant cancers. Larger studies in Chinese and Asian populations are needed to confirm these findings and the role of these risk loci in prostate cancer etiology in Asian men.

Genetic and epigenetic inactivation of TNFRSF10C in human prostate cancer.

BACKGROUND: TNFRSF10C, is located on 8p21.3, one of the most frequently deleted loci in the genome of prostate cancer (PCa). Hypermethylation of TNFRSF10C promoter CpG island (CGI) had been reported in many tumors including PCa. However, the interplay between somatic deletion and promoter hypermethylation of TNFRSF10C on PCa development has not been investigated. METHODS: Methylation status of promoter CGI and deletion status of the TNFRSF10C locus was investigated by bisulfite sequencing and Affymetrix SNP array, respectively, in 59 pairs of PCa tumor and matched normal samples with three PCa cell lines. TNFRSF10C gene expression changes in relation to cancer-associated genetic/epigenetic changes in clinical specimens, and change of TNFRSF10C expression before and after 5-aza-2'-deoxycytidine treatment in the PC3 PCa cell line was assessed by real-time RT-PCR. RESULTS: We found that TNFRSF10C promoter CGI was differentially methylated in 46 of 59 primary cancers (78.0%). Hemizygous deletion at TNFRSF10C was found in 44 of the 59 prostate tumors (74.5%). Interestingly, in 94.9% of the tumors (56 out of 59), TNFRSF10C was either hemizygously deleted or its promoter CGI hypermethylated. Deletion and/or methylation of the TNFRSF10C gene were correlated with decreased mRNA expression of the gene in clinical specimens. Demethylation of the TNFRSF10C promoter CGI was accompanied by transcriptional re-activation of TNFRSF10C in the PCa cell line PC3. CONCLUSION: We found a notably high frequency of promoter CGI methylation and deletion of TNFRSF10C in PCa tissues. Our results indicated that inactivation of TNFRSF10C by chromosomal deletion and promoter methylation may play an important role in PCa development.

Genetic variation in the toll-like receptor gene cluster (TLR10-TLR1-TLR6) and prostate cancer risk.

Toll-like receptors (TLRs) are key players in the innate immune system and initiate the inflammatory response to foreign pathogens such as bacteria, fungi and viruses. The proposed role of chronic inflammation in prostate carcinogenesis has prompted investigation into the association of common genetic variation in TLRs with the risk of this cancer. We investigated the role of common SNPs in a gene cluster encoding the TLR10, TLR6 and TLR1 proteins in prostate cancer etiology among 1,414 cancer cases and 1,414 matched controls from the Cancer Prevention Study II Nutrition Cohort. Twenty-eight SNPs, which included the majority of the common nonsynonymous SNPs in the 54-kb gene region and haplotype-tagging SNPs that defined 5 specific haplotype blocks, were genotyped and their association with prostate cancer risk determined. Two SNPs in TLR10 [I369L (rs11096955) and N241H (rs11096957)] and 4 SNPs in TLR1 [N248S (rs4833095), S26L (rs5743596), rs5743595 and rs5743551] were associated with a statistically significant reduced risk of prostate cancer of 29-38% (for the homozygous variant genotype). The association of these SNPs was similar when the analysis was limited to cases with advanced prostate cancer. Haplotype analysis and linkage disequilibrium findings revealed that the 6 associated SNPs were not independent and represent a single association with reduced prostate cancer risk (OR = 0.55, 95% CI: 0.33, 0.90). Our study suggest that a common haplotype in the TLR10-TLR1-TLR6 gene cluster influences prostate cancer risk and clearly supports the need for further investigation of TLR genes in other populations.

RNA sequencing reveals upregulation of RUNX1-RUNX1T1 gene signatures in clear cell renal cell carcinoma.

In the past few years, therapies targeted at the von Hippel-Lindau (VHL) and hypoxia-inducible factor (HIF) pathways, such as sunitinib and sorafenib, have been developed to treat clear cell renal cell carcinoma (ccRCC). However, the majority of patients will eventually show resistance to antiangiogenesis therapies. The purpose of our study was to identify novel pathways that could be potentially used as targets for new therapies. Whole transcriptome sequencing (RNA-Seq) was conducted on eight matched tumor and adjacent normal tissue samples. A novel RUNX1-RUNX1T1 pathway was identified which was upregulated in ccRCC through gene set enrichment analysis (GSEA). We also confirmed the findings based on previously published gene expression microarray data. Our data shows that upregulated of the RUNX1-RUNX1T1 gene set maybe an important factor contributing to the etiology of ccRCC.

Genome-wide association study identifies genetic determinants of urine PCA3 levels in men.

Prostate cancer gene 3 (PCA3) is a non-coding gene specifically overexpressed in prostate cancer (PCa) that has great potential as a clinical biomarker for predicting prostate biopsy outcome. However, genetic determinants of PCA3 expression level remain unknown. To investigate the association between genetic variants and PCA3 mRNA level, a genome-wide association study was conducted in 1371 men of European descent in the REduction by DUtasteride of prostate Cancer Events trial. First-voided urine specimens containing prostate cells were obtained after digital rectal examination. The PROGENSA PCA3 assay was used to determine PCA3 score in the urinary samples. A linear regression model was used to detect the associations between (single nucleotide polymorphisms) SNPs and PCA3 score under an additive genetic model, adjusting for age and population stratification. Two SNPs, rs10993994 in ß-microseminoprotein at 10q11.23 and rs10424878 in kallikrein-related peptidase 2 at 19q13.33, were associated with PCA3 score at genome-wide significance level (P = 1.22 x 10(-9) and 1.06 x 10(-8), respectively). Men carrying the rs10993994 "T" allele or rs10424878 "A" allele had higher PCA3 score compared with men carrying rs10993994 "C" allele or rs10424878 "G" allele (ß = 1.25 and 1.24, respectively). This is the first comprehensive search for genetic determinants of PCA3 score. The novel loci identified may provide insight into the molecular mechanisms of PCA3 expression as a potential marker of PCa.

Genome-wide association study identifies loci at ATF7IP and KLK2 associated with percentage of circulating free PSA.

BACKGROUND: Percentage of free-to-total prostate-specific antigen (%fPSA) is an independent predictor of risk for prostate cancer among men with modestly elevated level of total PSA (tPSA) in blood. Physiological and pathological factors have been shown to influence the %fPSA value and diagnostic accuracy. MATERIALS/METHODS: To evaluate genetic determinants of %fPSA, we conducted a genome-wide association study of serum %fPSA by genotyping 642,584 single nucleotide polymorphisms (SNPs) in 3192 men of European ancestry, each with a tPSA level of 2.5 to 10 ng/ml, that were recruited in the REduction by DUtasteride of Prostate Cancer Events study. Single nucleotide polymorphisms (SNPs) with P < 10(-5) were further evaluated among the controls of a population-based case-control study in Sweden (2899 prostate cancer cases and 1722 male controls), including 464 controls having tPSA levels of 2.5 to 10 ng/ml. RESULTS: We identified two loci that were associated with %fPSA at a genome-wide significance level (P <5 x 10(-8)). The first associated SNP was rs3213764 (P = 6.45 x 10(-10)), a nonsynonymous variant (K530R) in the ATF7IP gene at 12p13. This variant was also nominally associated with tPSA (P = .015). The second locus was rs1354774 (P = 1.25 x 10(-12)), near KLK2 at 19q13, which was not associated with tPSA levels, and is separate from the rs17632542 locus at KLK3 that was previously associated with tPSA levels and prostate cancer risk. Neither rs3213764 nor rs1354774 was associated with prostate cancer risk or aggressiveness. CONCLUSIONS: These findings demonstrate that genetic variants at ATF7IP and KLK2 contribute to the variance of %fPSA.

Variation in IL10 and other genes involved in the immune response and in oxidation and prostate cancer recurrence.

BACKGROUND: To evaluate the association of variation in genes involved in immune response, including IL10, production and detoxification of reactive oxygen species, and repair of oxidative DNA damage with risk of recurrence after surgery for localized prostate cancer. METHODS: We conducted a nested case-control study of men who had a radical prostatectomy in 1993 to 2001. A total of 484 recurrence cases and 484 controls were matched on age, race, and pathologic stage and grade. Germline DNA was extracted from paraffin-embedded unaffected lymph nodes. We genotyped candidate single-nucleotide polymorphisms (SNP) in IL10, CRP, GPX1, GSR, GSTP1, hOGG1, IL1B, IL1RN, IL6, IL8, MPO, NOS2, NOS3, SOD1, SOD2, SOD3, TLR4, and TNF and tagging SNPs in IL10, CRP, GSR, IL1RN, IL6, NOS2, and NOS3. We used conditional logistic regression to estimate OR and 95% confidence intervals (CI). RESULTS: The minor allele (A) in IL10 rs1800872, known to produce less interleukin-10 (IL-10), was associated with a higher risk of recurrence (OR = 1.76, 95% CI: 1.00-3.10), and the minor allele (G) in rs1800896, known to produce more IL-10, was associated with a lower risk of recurrence (OR = 0.66, 95% CI: 0.48-0.91). We also observed associations for candidate SNPs in CRP, GSTP1, and IL1B. A common IL10 haplotype and 2 common NOS2 haplotypes were associated with recurrence. CONCLUSION: Variation in IL10, CRP, GSTP1, IL1B, and NOS2 was associated with prostate cancer recurrence independent of pathologic prognostic factors. IMPACT: This study supports that genetic variation in immune response and oxidation influence prostate cancer recurrence risk and suggests genetic variation in these pathways may inform prognosis.

Evaluation of PPP2R2A as a prostate cancer susceptibility gene: a comprehensive germline and somatic study.

PPP2R2A, mapped to 8p21.2, codes for the α isoform of the regulatory B55 subfamily of protein phosphatase 2 (PP2A). PP2A is one of the four major serine/threonine phosphatases and is implicated in the negative control of cell growth and division. Because of its known functions and location within a chromosomal region where evidence for linkage and somatic loss of heterozygosity was found, we hypothesized that either somatic copy number changes or germline sequence variants in PPP2R2A may increase prostate cancer (PCa) risk. We examined PPP2R2A deletion status in 141 PCa samples using Affymetrix SNP arrays. It was found that PPP2R2A was commonly (67.1%) deleted in tumor samples, including a homozygous deletion in three tumors (2.1%). We performed a mutation screen for PPP2R2A in 96 probands of hereditary prostate cancer families. No high risk mutations were identified. In addition, we re-analyzed 10 SNPs of PPP2R2A in sporadic PCa cases and controls. No significant differences in the allele and genotype frequencies were observed among either PCa cases and controls or PCa aggressive and non-aggressive cases. Taken together, these results suggest that a somatic deletion rather than germline sequence variants of PPP2R2A may play a more important role in PCa susceptibility.

Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality.

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 (P(trend) = 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.

Prostate cancer risk associated loci in African Americans.

Four genome-wide association studies, all in populations of European descent, have identified 20 independent single nucleotide polymorphisms (SNP) in 20 regions that are associated with prostate cancer risk. We evaluated these 20 SNPs in a combined African American (AA) study, with 868 prostate cancer patients and 878 control subjects. For 17 of these 20 SNPs, implicated risk-associated alleles were found to be more common in these AA cases than controls, significantly more than expected under the null hypothesis (P = 0.03). Two of these 17 SNPs, located at 3p12, and region 2 at 8q24, were significantly associated with prostate cancer risk (P < 0.05), and only SNP rs16901979 at region 2 of 8q24 remained significant after accounting for 20 tests. A multivariate analysis of additional SNPs across the broader 8q24 region revealed three independent prostate cancer risk-associated SNPs, including rs16901979, rs13254738, and rs10086908. The first two SNPs were approximately 20 kb apart and the last SNP, a novel finding from this study, was approximately 100 kb centromeric to the first two SNPs. These results suggest that a systematic evaluation of regions harboring known prostate cancer risk SNPs implicated in other races is an efficient approach to identify risk alleles for AA. However, studies with larger numbers of AA subjects are needed, and this will likely require a major collaborative effort to combine multiple AA study populations.

Sequence variants at 22q13 are associated with prostate cancer risk.

To search for genetic variants that are associated with prostate cancer risk in the genome, we combined the data from our genome-wide association study (GWAS) in a population-based case-control study in Sweden with publicly available GWAS data from the Cancer Genetic Markers of Susceptibility (CGEMS) study. We limited the cases to those with aggressive disease in an attempt to identify risk variants that are associated with this most clinically relevant form of the disease. Among the most likely candidate single nucleotide polymorphisms (SNP) identified from the two GWAS, we sequentially confirmed one SNP at 22q13 in two independent study populations: the remaining subjects in Cancer of the Prostate in Sweden and a hospital-based case-control study at Johns Hopkins Hospital. Association of aggressive prostate cancer with the SNP at 22q13 was also observed in the publicly available data of four additional study populations from the second stage of the CGEMS study. In all seven study populations examined, the frequency of allele "C" of rs9623117 at 22q13 was consistently higher in aggressive cases than in controls. The combined allelic test was highly significant, with P = 5.0 x 10(-7). The odds ratio (OR) of allele C for aggressive prostate cancer was estimated to be 1.18 [95% confidence interval (95% CI), 1.11-1.26]. However, the SNP was also associated with nonaggressive prostate cancer, with an estimated OR of 1.11 (95% CI, 1.04-1.19; P = 0.004). The risk-associated variants are located within the genomic region of TNRC6B, a gene involved in miRNA-mediated mRNA degradation. Additional studies are warranted to further confirm the association.