rs4430796

This genome-wide association study of 2511 familial prostate cancer cases and 1382 controls identified significant associations in six regions previously linked to prostate cancer risk. Most notably, rs138042437 at 8q24.21 achieved an exceptionally large effect size (OR=13.3, p=1.7e-8) and demonstrated strong co-segregation with disease in 116 affected relatives (p=8.5e-11). The study identified a rare segregating haplotype at 8q24.21 containing three SNPs (rs183373024, rs188140481, rs138042437) that characterized a prostate cancer predisposition locus.

Developed a multi-state genetic variant-based Markov model for personalized prostate cancer risk stratification using Finnish population data. The model incorporates three primary SNPs (rs4242382 OR=1.75, rs138213197 OR=3.60, rs200331695 OR=6.0) and an extended panel of genetic variants to predict 10-year PCa risk ranging from 43% in the top 5% risk group to 11% in the bottom 60%, with recommendations for age-optimized screening (47 years for highest risk vs 55+ years for average/low risk) and risk-adapted interscreening intervals (< 1 year to 6+ years).

A case-case association study of 18,343 prostate cancer patients (16,515 European, 1,828 African-American) evaluating 36 validated PC-risk SNPs found that rs2735839 (G allele) on chromosome 19q13 in the KLK3 gene was significantly and inversely associated with aggressive disease and high Gleason scores in both populations (p = 9.343 × 10⁻⁸ overall, p = 1.042 × 10⁻⁵ European, p = 2.0 × 10⁻⁴ African-American).

Genome-wide association study of 474 prostate cancer cases and 458 controls from West African men identified a novel prostate cancer susceptibility locus at 10p14 marked by rs7918885 (p=1.29×10⁻⁷), localized to an intron of the lncRNA gene RP11-543F8.2. A stratified analysis by Gleason score revealed additional associations including rs34575154 in PCDHA1 at 5q31.3 (p=3.66×10⁻⁸) for high-grade disease and rs985081 at Xq28 (p=8.66×10⁻⁹) for low-grade disease. Validation in the African Ancestry Prostate Cancer GWAS Consortium showed limited replication, with only rs2993385 at 10p14 reaching nominal significance (p<0.05), highlighting population-specific genetic architecture.

Genome-wide association study of endometrial cancer (7,077 cases, 16,343 controls) identifying replication of the known HNF1B locus (rs4430796, OR=0.82, P=4.3×10⁻¹¹) and a novel genome-wide significant association at the RNASET2 locus (rs9459805, OR=1.19, P=1.11×10⁻⁵). A suggestive locus at PRLR (prolactin receptor) was also identified.

In a case-control study of 4,548 Polish men undergoing prostate biopsy (1,834 with cancer), five SNPs showed significant associations with prostate cancer (rs1800629, rs1859962, rs1447295, rs4430796, rs11228565). Cancer detection rates increased from 29% in men with no variant alleles to 63% in men with 7+ risk alleles (OR=4.2, p=0.002). However, SNP data did not improve the predictive power of clinical factors (age, PSA, DRE) for detecting cancer (AUC 0.726 vs 0.735, p=0.4).

Of 40 SNPs previously associated with type 2 diabetes, 19 (48%) introduce or remove CpG sites. In 84 human pancreatic islet donors, all 16 analyzed CpG-SNPs showed statistically significant differential DNA methylation (p≤2.3×10⁻⁵). Several CpG-SNPs including rs391300 (SRR), rs5945326 (DUSP9), rs11708067 (ADCY5), rs5015480 (HHEX), rs13266634 (SLC30A8), rs1801214 (WFS1), rs564398 (CDKN2A), and rs2237895 (KCNQ1) were associated with differential gene expression, alternative splicing, or hormone secretion, suggesting DNA methylation-mediated mechanisms linking genetic variants to type 2 diabetes pathogenesis.

Analysis of 20 GWAS-identified prostate cancer susceptibility SNPs in 601 patients treated with androgen-deprivation therapy (ADT) found that rs16901979 at 8q24 was significantly associated with prostate cancer-specific mortality (HR = 0.63, 95% CI 0.45-0.87, p = 0.005) and rs7931342 at 11q13 was associated with mortality (HR = 0.65, 95% CI 0.43-0.98, p = 0.038). These variants may help predict survival outcomes in prostate cancer patients undergoing ADT treatment.

This study demonstrates that 13 of 14 previously identified prostate cancer risk SNPs are significantly associated with early-onset prostate cancer (EO PCa; diagnosed ≤55 years), with effect sizes ranging from OR=1.15 to OR=1.55 per risk allele. Early-onset cases carried significantly more cumulative risk alleles (mean 12.4) compared to older-onset CGEMS cases (mean 11.9; p=1.7×10⁻⁵), suggesting common genetic variants play an increased role in earlier disease manifestation.

Case-control study of 127 African American prostate cancer cases and 345 controls from the Flint Men's Health Study examining 24 SNPs previously associated with prostate cancer in European populations. Found nominal evidence (P<0.05) for association with three 8q24 SNPs (rs6983561 OR=1.55, rs16901979 OR=1.60, rs7000448 OR=1.41) and two 10q11 SNPs (rs7904463, rs10740051 OR=0.51), replicating 8q24 findings in African Americans and providing first evidence for MSMB region association in this population.

This GWAS replication study evaluated 800 SNPs in African American (n=417) and European American (n=455) prostate cancer cases versus controls (n=925 AA, n=1,687 EA) from the NC-LA Prostate Cancer Project. Of 32 European-based GWAS SNPs, 13 were significant at P<0.05 in European Americans and 4 in African Americans (rs6983267, rs7017300, rs1859962, rs6501455). Two additional SNPs reached study-wide significance: rs1472606 (OR=1.43 in EA) and rs9351265 (OR=1.48 in AA). The study confirms a large proportion of cancer-associated regions from European GWAS but shows limited predictive value (AUC=0.60 in EA, 0.56 in AA) for clinical screening.

This methods paper presents a novel retrospective likelihood approach for estimating genotype relative risks from ascertained pedigrees, which adjusts for ascertainment bias by conditioning on the phenotypes of all pedigree members. The authors apply this method to 28 previously reported prostate cancer SNPs in Mayo Clinic pedigree data (469 affected men) and case-control samples (661 cases, 518 controls), demonstrating that relative risk estimates from pedigrees are consistent with odds ratios from case-control studies.

This meta-analysis of genome-wide association studies identified 30 prostate cancer risk-associated SNPs in Caucasian populations. The SNPs had odds ratios ranging from 1.12-1.47, except rs16901979 (OR=1.80). These 30 SNPs collectively explained approximately 13.5% of the total genetic variance in prostate cancer risk, with individual SNPs explaining 0.2-0.9% of variance.

A nested case-control study in two prospective cohorts (CPS-II and PLCO) examining whether HNF1B and JAZF1 variants associated with both diabetes and prostate cancer mediate the inverse relationship between these diseases. Three HNF1B SNPs (rs11649743, rs4430796, rs7501939) were associated with decreased prostate cancer risk (OR 0.84-0.86) and marginally increased diabetes risk, while two JAZF1 SNPs (rs6968704, rs10486567) were associated with decreased prostate cancer risk but not diabetes. The associations persisted after stratification by diabetic status, indicating that diabetes does not mediate the SNP-prostate cancer relationships.

This population-based case-control study evaluated 17 prostate cancer susceptibility loci identified in European GWAS populations in Chinese men (288 cases, 155 controls from Shanghai). Two of 17 loci on chromosome 8q24 showed significant associations with prostate cancer risk (rs1016343: OR=2.07, P=9.4×10⁻⁴; rs10090154: OR=2.07, P=0.002). Multiple additional SNPs at 8q24 regions 1 and 2 were also significantly associated with prostate cancer risk, while region 3 SNPs showed mostly null associations. Results suggest that prostate cancer risk variants identified in European populations are also relevant for Chinese men.

This case-case study of 5,895 prostate cancer patients from Johns Hopkins Hospital examined 20 genome-wide association study (GWAS)-identified risk SNPs for association with clinicopathologic variables of cancer aggressiveness. Only rs2735839 in KLK3 (p = 8.4 × 10⁻⁷) and rs10993994 in MSMB (p = 0.046) showed significant associations, but notably with the risk alleles being more frequent in less aggressive rather than more aggressive disease, likely reflecting PSA detection bias. The vast majority of the 20 tested SNPs showed no association with Gleason score, tumor stage, or aggressive disease phenotypes, suggesting they identify overall prostate cancer risk rather than aggressiveness.

This study tests the thrifty genotype hypothesis by examining 17 confirmed type 2 diabetes susceptibility loci and 13 obesity-susceptibility loci for signatures of positive selection. Using ancestral/derived allele analysis, integrated haplotype scores (iHS), and population differentiation (FST), the authors found limited evidence supporting the thrifty genotype hypothesis. Only rs7901695 at TCF7L2 showed notably elevated FST values (0.579 between JPT+CHB and YRI populations), and FTO showed the strongest selection signal among obesity loci (iHS=1.991).

A population-based case-control study tested whether five SNPs at chromosomal regions 8q24, 17q12, and 17q24.3, combined with family history, predict prostate cancer risk and mortality in Caucasians from King County, Washington (1,308 cases, 1,266 controls). Combined SNP genotypes and family history were significantly associated with prostate cancer risk (p trend = 1.5 × 10⁻²⁰), with men carrying ≥5 risk factors showing OR of 4.9 (95% CI 1.6–18.5). However, these factors did not improve prediction models after accounting for known risk predictors and were not associated with prostate cancer-specific mortality.

This study confirms a strong cumulative effect of five genetic variants on prostate cancer risk across three populations: CAPS (Swedish), Johns Hopkins Hospital (JHH), and CGEMS-prostate (U.S.). Men carrying combinations of 1, 2, 3, and 4+ risk alleles had odds ratios of 1.41 (1.20-1.67), 1.88 (1.59-2.22), 2.36 (1.95-2.85), and 3.80 (2.77-5.22) respectively. When family history was included as a sixth risk factor, the cumulative effect was even stronger, with men carrying 5+ risk factors showing OR of 11.26 (4.74-24.75).