rs1447295

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.

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).

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).

This exome array study of 776 Korean prostate cancer patients identified eight SNPs (rs77080351 OR 7.23, rs200944490 OR 5.24, rs2071292 OR 3.37, rs117237810 OR 4.86, rs191118242 OR 5.10, rs4965121 OR 2.44, rs61742396 OR 3.24, and rs6573513 OR 1.72) significantly associated with biochemical recurrence after radical prostatectomy. Adding genetic information to clinicopathological models increased predictive accuracy from 85.1% to 89.0% (P=0.025).

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).

A meta-analysis of 78 case-control studies (73,996 cases, 96,741 controls) found that the rs6983267 polymorphism on chromosome 8q24 was significantly associated with increased cancer risk across all genetic models (dominant: OR=1.19, 95% CI=1.13-1.26; recessive: OR=1.19, 95% CI=1.14-1.25; homozygous: OR=1.31, 95% CI=1.23-1.40). Stratified analyses showed significant associations for colorectal cancer, prostate cancer, and thyroid cancer in Caucasians, and lung cancer in Asians.

Meta-analysis of 78 case-control studies (73,996 cases, 96,741 controls, 170,737 total subjects) examining the association between 8q24 rs6983267 G/T polymorphism and cancer susceptibility. The G risk allele was significantly associated with increased cancer risk across all genetic models (dominant: OR=1.19, 95%CI=1.13-1.26; recessive: OR=1.19, 95%CI=1.14-1.25; homozygous: OR=1.31, 95%CI=1.23-1.40). Significant associations were found for colorectal cancer, prostate cancer, thyroid cancer, and lung cancer in ethnicity-stratified analyses.

A candidate region association study of 10 previously reported 8q24 SNPs in African-Barbadian men from the Prostate Cancer in a Black Population (PCBP) study found one significant association with prostate cancer. Rs2124036 homozygous C/C genotype showed significant association with prostate cancer risk (OR = 2.7, 95% CI 1.3-5.3, P = 0.005). Meta-analysis across three Caribbean populations (Barbados, Jamaica, Tobago) for rs16901979 and rs1447295 identified rs16901979 A allele as significantly associated (Z = 2.73, p = 0.006, OR = 1.31, 95% CI 1.09-1.58).

This study examined 10 chromosome 8q24 SNPs in 1,157 men (308 prostate cancer cases, 469 controls from West Africa, and additional Caribbean and population samples) to determine the prevalence and risk magnitude of 8q24 variants in populations of African descent. The study replicated associations between prostate cancer risk and rs6983561 (OR=0.6, P=0.03), rs16901979 (OR=1.6, P=0.03), and rs7008482 (OR=2.3) in West African men, with no significant heterogeneity of effects across African descent populations.

This case-control study evaluated 157 tag SNPs in the 8q24 chromosomal region in relation to papillary thyroid cancer (PTC) risk using 344 PTC cases and 452 controls. While previously cancer-associated SNPs (rs1562430, rs1447295, rs6983267) showed no significant association with PTC, one SNP (rs4733616, P=0.003) and 12 others showed uncorrected P<0.05 associations; however, none remained significant after false discovery rate correction, suggesting no strong association between 8q24 variants and sporadic PTC risk.

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.

A case-control study of 489 prostate cancer cases and 427 controls in a New Zealand Caucasian population examined 15 chromosome 8q24 SNPs. Four SNPs showed statistically significant associations with prostate cancer risk: rs10086908 (T allele, OR=1.64), rs16901979 (A allele, OR=2.58), rs1447295 (A allele, OR=1.70), and rs4242382 (A allele, OR=1.60). A weighted genetic risk score based on all 15 SNPs was significantly associated with prostate cancer risk (OR=1.10), with smoking contributing additional risk.

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.

Case-control study in 354 Tobago men with screening-detected prostate cancer and 438 controls examining associations between chromosome 8q24 variants and prostate cancer risk. SNP rs16901979 showed significantly increased prostate cancer risk (OR=1.41, 95% CI 1.02-1.95, P=0.04), with stronger association in early-onset prostate cancer (OR=2.37, 95% CI 1.40-3.99, P=0.001). SNPs rs1447295 and rs6983267 showed no overall association, but rs1447295 showed tendencies toward increased risk in early-onset cases.

Systematic literature review of 22 GWAS studies identifying 53 SNPs in 29 genomic loci associated with aggressive and progressive prostate cancer, particularly in low-grade disease. Functional analysis of 21 SNPs revealed involvement in the MYC/POU5F1B pathway (rs1447295, rs6983267, rs4242382), androgen receptor pathway (rs17021918, rs10486567, rs7679673, rs2939244), and PSA/KLK3 biomarkers (rs2735839, rs10993994). SNPs were integrated with somatic copy number aberration data, with 17 SNPs found in regions of recurrent CNAs predictive of progression; notably, rs1447295 and 7 other SNPs cluster in 8q24 gain regions harboring MYC.

This comprehensive review examines genetic association studies on prostate cancer, discussing GWASs that have identified over 75 variants associated with PCa risk (as of February 2016), with major susceptibility regions at 8q24, 17q12, 17q24, 10q11, and 19q13. The paper also reviews candidate gene-based approaches targeting genes involved in androgen signaling, carcinogen metabolism, DNA repair, vitamin D signaling, inflammation, angiogenesis, and cellular adhesion, as well as regulatory RNA genes.

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 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.

This case-control study of 596 prostate cancer cases and 567 controls tested 49 tagging SNPs in the 8q24 region for association with prostate cancer susceptibility and tumor aggressiveness in men of European ancestry. After multiple testing correction, four SNPs showed significant association with PC susceptibility (rs1016342, rs1378897, rs871135, rs6470517), while rs6470517 was significantly associated with aggressive tumor phenotypes (Gleason score and TNM staging, P = 10^-4 to 10^-5). Meta-analysis of rs1447295 showed a pooled odds ratio of 1.38 (95% CI: 1.30-1.46).

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.

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 systematic review identified 53 unique SNPs in 29 genomic loci associated with aggressive prostate cancer progression and poor outcomes from GWAS studies. Functional studies implicated 21 SNPs as modulating the androgen receptor pathway, MYC oncogene, and PSA-related genes, with rs1447295 and rs10993994 being replicated across multiple populations and associated with unfavorable pathological features in low-grade prostate cancer.

This case-control study investigated 15 SNPs at the 8q24 locus for association with testicular germ cell tumors (TGCT) using 568 cases and 680 controls from the STEED military study. Overall, no significant associations were found between 8q24 SNPs and TGCT risk. However, nonseminomas showed three tentative associations: rs6470494 (OR=1.68 for GG genotype, p=0.04), rs13254738 (OR=1.62 for TT genotype, p=0.07), and an inverse association with rs10505476 (OR=0.67 for CT genotype, p=0.04).

This comprehensive resequence analysis of a 136 kb region of chromosome 8q24 (chr8: 128,473,000-128,609,802) using 454 next-generation sequencing identified 442 novel SNPs and characterized the complete catalog of common variation across regions previously associated with prostate and colorectal cancer risk by GWAS. The study identified 780 common SNPs, with 454 having MAF ≥5%, and determined that 114 tag SNPs are necessary to comprehensively tag the region (r² > 0.8), providing important resources for fine-mapping association signals marked by rs6983267 and rs1447295.

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).

Family-based association study of 1,015 non-Hispanic white men from 403 familial and early-onset prostate cancer families examining chromosome 8q24 markers. rs6983561 (minor 'C' allele, OR=2.26) and rs6983267 (major 'G' allele, OR=1.30) showed significant associations with prostate cancer risk. rs6983561 was specifically associated with early-onset disease (age <50, p=0.03) with OR=4.69, while rs6983267 was associated with clinically aggressive disease (p=0.007) with OR=1.90.