rs10993994

This review explores applications of the CRISPR-Cas system in tumor biology, including tumor model construction (cellular and in vivo), cancer mechanism research, drug delivery systems, immunotherapy, and genome-wide screening for novel drug targets. The paper discusses how CRISPR-Cas enables rapid development of cell, organoid, and animal cancer models to study genetic determinants of tumor development and identifies therapeutic opportunities.

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.

This study integrated ChIP-seq analysis of androgen receptor-binding sites in prostate cancer cells with GWAS data and found that rs11891426:T>G in the melanophilin gene (MLPH) lies within a functional AR-binding motif, with the risk G allele attenuating transcriptional activity. Expression analysis showed MLPH was significantly lower in tumors carrying the G allele, suggesting a tumor-suppressive role weakened by this functional variant.

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).

This review examines the MSMB gene variant rs10993994 and its association with prostate cancer risk, where T allele carriers have approximately 25% increased risk per allele (OR=1.57 for TT homozygotes). The authors propose two mechanisms for the protective effect of the C allele: tumor suppression through PSP94 and a novel hypothesis involving pathogen defense against intracellular fungal infections in the prostate.

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.

In a population-based study of 1,323 prostate cancer cases and 1,268 controls, the MSMB promoter SNP rs10993994:C>T was associated with increased prostate cancer risk (OR=1.31), with the variant allele associated with decreased PSP94 protein expression, particularly in tumor tissue. The NCOA4 SNP rs7350420:T>C showed a 15% reduction in cancer risk (OR=0.85, p=5.6×10⁻³), but this association was not independent of rs10993994:C>T. Protein expression analyses of 519 prostate tissue samples confirmed rs10993994:C>T's primary effect on PSP94 levels, with moderate associations observed for rs10761618:T>C and rs7085433:G>A with NCOA4 expression.

A two-stage GWAS in 3,495 Chinese men (Stage 1: N=1,999; Stage 2: N=1,496) identified three genetic regions associated with prostate-specific antigen (PSA) levels: a novel locus at 1q32.1 (SLC45A3, rs12409639, P=8.43×10⁻¹²) with 20% increase per allele, and two previously reported loci at 10q11.23 (MSMB, rs10993994) and 19q13.33 (KLK3, rs2735839). Combined P-values ranged from 4.62×10⁻¹⁷ to 6.45×10⁻³⁷. The novel SLC45A3 variant was associated with PSA but not prostate cancer risk.

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.

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.

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 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 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 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.

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 case-control study in southern Chinese Han population (251 cases, 258 controls) confirms the association of rs10993994 with prostate cancer risk, finding the T allele associated with increased prostate cancer risk (OR=1.30, 95% CI=1.01-1.67, P=0.040). The T allele was also associated with lower serum MSMB expression levels, supporting a functional mechanism involving reduced expression of the putative tumor suppressor gene MSMB encoded in this promoter region.

This paper applies a bias correction method for odds ratio estimates from GWAS discovery data, demonstrating that the 'winner's curse' affects initial effect size estimates. The authors applied conditional maximum likelihood estimation to correct bias in GWAS findings from multiple complex diseases (breast cancer, colorectal cancer, lung cancer, prostate cancer, type I and II diabetes) and show that bias-adjusted odds ratios are substantially more consistent with subsequent replication studies, with selection-adjusted confidence intervals providing better uncertainty quantification than uncorrected estimates.

This comprehensive resequence analysis of a 97 kb region on chromosome 10q11.2 containing the MSMB gene identified 241 novel polymorphisms in 70 individuals (36 prostate cancer cases, 26 controls of European origin, and 8 CEPH individuals). The study extensively characterized genetic variation in the 51 kb linkage disequilibrium block containing rs10993994 (the prostate cancer risk-associated SNP with OR=1.20, p=9.7×10⁻¹⁹), providing comprehensive coverage for fine-mapping studies of prostate cancer susceptibility.

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 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.