rs1042522

This four-center case-control study examined associations between H19 gene polymorphisms and Wilms tumor risk in 355 Chinese children with Wilms tumor and 1,070 cancer-free controls. Three H19 polymorphisms (rs2839698 G>A, rs3024270 C>G, rs217727 G>A) were significantly associated with Wilms tumor susceptibility. The rs2839698 AA genotype showed OR=1.52 (p=0.027) for increased risk, rs3024270 CG showed protective effect OR=0.61 (p=0.0007), and carriers of multiple risk genotypes had OR=1.84 (p=0.001) for 2 risk genotypes.

Case-control study of 366 POAG patients and 352 controls in a Chinese population found that rs4938723 C/T polymorphism in the miR-34b promoter is associated with reduced primary open-angle glaucoma (POAG) risk. CT/CC genotypes showed significantly decreased POAG risk (OR 1.89, 95% CI 1.40-2.54, p<0.0001), while CC homozygotes had the strongest protective effect (OR 2.28, p=0.0029). Functional studies demonstrated that the C allele increases miR-34b promoter activity and suppresses TP53 expression, reducing retinal ganglion cell apoptosis.

A comprehensive meta-analysis of 50 case-control studies from the Indian subcontinent identified genetic variants modifying lung cancer risk, finding FDR-corrected associations for rs3547/XRCC1 (OR=1.83-2.72) and rs1048943/CYP1A1 (OR=2.07). The rs1048943/CYP1A1 variant showed strongest associations with adenocarcinoma (OR=3.38) and squamous cell carcinoma (OR=3.53) with significant effect modification by smoking status. Global meta-analysis confirmed rs1048943/CYP1A1 association across world populations (OR=1.22, p=0.01).

In a retrospective study of 453 lung cancer patients (328 adenocarcinoma, 107 squamous cell carcinoma), the MDM2 c.309T>G polymorphism (rs2279744) showed an association with prognosis. The MDM2 T/T genotype was a significant independent prognostic factor for worse overall survival in stage I adenocarcinoma patients (HR = 2.23, 95% CI: 1.07-4.65, P = 0.03), while showing no significant association in the overall population or in squamous cell carcinoma.

Population-based case-control study of 7,079 cancer cases and 3,747 controls examined MDM4 SNP34091 (rs4245739) associations with breast, colon, lung, and prostate cancer risk. MDM4 SNP34091C was associated with marginally reduced breast cancer risk in recessive model (OR=0.77, 95% CI=0.59-0.99), and more strongly reduced risk when combined with MDM2 SNP309GG genotype (OR=0.41, 95% CI=0.21-0.82). No significant associations were found for colon, lung, or prostate cancer.

This case-control study of 67 salivary gland tumors (35 malignant, 32 benign) compared with healthy controls found that the rs1042522 Arg allele in TP53 codon 72 was more frequent in malignant tumors (OR=3.15, p=0.0023), with the Arg/Arg genotype conferring substantially increased risk (OR=7.18, p<0.0001). However, the SNP did not correlate with age of onset or transcriptional levels of apoptotic genes (BAX, CASPASE-3, BCL-2).

A hospital-based case-control study in rural and urban India (1,204 cases; 1,212 controls) examined genetic and lifestyle risk factors for breast cancer. Four SNPs in FGFR2 (rs1219648, rs2420946, rs2981575, rs2981582) showed positive associations with breast cancer (ORs 1.32-1.47). Additional SNPs in obesity and metabolic genes (rs374748 in FBN2, rs2922763 in HNF4G, rs2116830 in KCNMA1, rs11121832 in MTHFR, rs16886165 in MAP3K1, rs11594610 in TCF7L2, rs2274459 in MLN) were associated with increased breast cancer risk. Waist-to-hip ratio ≥0.95 showed strong association (OR 3.78; 95% CI 2.92-4.89), and women living first 20 years in rural areas showed protective effect (OR 0.77).

A cohort study of 940 gastric adenocarcinoma patients examined the association between TP53 codon 72 polymorphism (rs1042522, Arg72Pro) and MDM2 SNP309 (rs2279744) with survival outcomes. TP53 codon 72 polymorphism was significantly associated with poor survival in patients receiving 5-fluorouracil-based postoperative chemotherapy (adjusted HR=1.63, 95% CI=1.08-2.44), with particularly strong associations in the FOLFOX regimen (adjusted HR=4.47, 95% CI=1.21-16.55). MDM2 SNP309 showed no significant association with survival.

This case-control association study evaluated 23 genetic sequence variants in 17 genes across DNA repair, cell cycle, and other pathways in 531 stage I-II radiation-treated head and neck cancer (HNC) patients to identify associations with secondary primary cancers (SPCs). Among the variants tested, the DNMT3B C149T variant (rs2424913) showed a strong significant association with SPC development, with adjusted hazard ratios of 2.23 (95% CI, 1.32-3.78; P = .003) for TT versus CC genotype and 1.49 (95% CI, 1.15-1.95; P = .003) per T allele. A haplotype cluster of 5 DNMT3B variants in strong linkage disequilibrium also showed significant associations (P < .003), suggesting aberrant DNA methylation is an important modulator of field cancerization in HNC.

Case-control study (325 cases, 335 controls) examining seven polymorphisms in p53-related genes (p53 codon 72 Arg/Pro, p73 4/14 GC/AT, MDM2 A2164G and T2580G, MDM4 rs11801299, rs10900598, rs1380576) and HPV16 seropositivity for oral cancer risk. Combined risk genotypes with HPV16 seropositivity showed substantially increased oral cancer risk (OR 2.1-19.1), with strongest effects in younger subjects, never-smokers, and oropharyngeal cancer patients.

This association study of 377 Korean colorectal cancer patients examined 15 SNPs in 12 apoptosis-related genes as prognostic markers for survival after curative resection. RIPK1 rs2272990 (GA/AA genotype, HR=2.093, p=0.007) and CASP7 rs2227310 (GG genotype, HR=2.641, p=0.002) were significantly associated with worse disease-free survival in multivariate analysis, with similar associations for disease-specific survival. The polymorphisms showed stronger associations in colon cancer than rectal cancer.

This comprehensive review examines the genomics of schizophrenia and pharmacogenomics of antipsychotic drugs, synthesizing evidence on over 200 genes associated with psychotic disorders. The authors discuss five categories of genes relevant to antipsychotic response: disease-associated genes, mechanism-of-action genes, drug metabolism genes (particularly CYP2D6, CYP2C19, CYP2C9, CYP3A4), drug transporter genes, and pleiotropic genes. The review details pharmacogenomic profiles of 20+ antipsychotic drugs and demonstrates significant ethnic and interindividual variation in drug metabolism phenotypes, with examples including CYP2D6 extensive metabolizers (55.71% of population), intermediate metabolizers (34.7%), poor metabolizers (2.28%), and ultra-rapid metabolizers (7.31%).

In 90 DLBCL patients treated with R-CHOP chemotherapy, polymorphisms in apoptosis-related genes were analyzed. The AA genotype of LTA C804A (rs1041981) was associated with worse time to progression (HR = 7.92; 95% CI = 1.42-44.18; P = 0.018), as was the GG genotype of RIPK1 G83A (rs2272990) (HR = 20.02; 95% CI = 1.59-251.52; P = 0.018). These polymorphisms may serve as prognostic markers for DLBCL treated with R-CHOP.

Case-control study examining the association between the p53 Pro72Arg polymorphism (rs1042522) and prostate cancer risk in African American men (266 cases, 196 controls). The G allele (Arg) showed significant association with increased PCa risk in the dominant model (OR = 1.53, 95% CI: 1.02-2.29, P = 0.04) and log-additive model (OR = 1.33, 95% CI: 0.99-1.78, P = 0.06), though significance was attenuated after age adjustment. The study is the first to examine this polymorphism in African American men and suggests population-dependent allele frequency differences may be relevant to understanding prostate cancer health disparities.

This German case-control study (275 breast cancer cases, 275 controls) examined associations between two SNPs in TP53 (R72P/rs1042522) and p21 (S31R/ss4388499) genes with breast cancer risk. The TP53 variant showed no significant association (p=0.945), but the p21 CA genotype was significantly more frequent in cases versus controls (OR=1.74, 95% CI=1.00-3.05, p=0.034), though the authors concluded p21 does not appear to be an exclusive prognostic marker.

A case-control association study of 240 early breast cancer patients examining 12 SNPs in apoptosis-related genes found that TNFSF10 rs1131532 (F275F) was significantly associated with poor survival outcomes, with the TT genotype showing worse disease-free survival (HR = 3.304, P = 0.002), distant disease-free survival (HR = 4.757, P = 0.001), and overall survival (HR = 4.691, P = 0.002). PTGS2 rs5275 was also associated with distant disease-free survival (HR = 0.302, P = 0.041).

Hospital-based case-control study of 453 breast cancer patients and 461 controls in a Spanish population examining TP53 polymorphisms. The Arg72Pro (Ex4 ± 119G/C, rs1042522) TP53 polymorphism was significantly associated with increased breast cancer risk (OR=1.34, 95% CI 1.03-1.75, p=0.029). The two-locus interaction between this TP53 variant and -710 C/T VEGFR1 showed even stronger association (OR=1.44, 95% CI 1.10-1.88, p=0.0083). Pro/Pro carriers at rs1042522 also showed poor disease-free survival (p=0.013).

This pathological study examined distal fallopian tube epithelium from two Li-Fraumeni syndrome (LFS) patients carrying germline TP53 mutations. Fallopian tubes showed markedly increased frequency of p53 signatures (10-20 per section) compared to the general population, with 55% showing loss of heterozygosity (LOH) at the TP53 locus. The findings demonstrate that germline TP53 mutations predispose to focal epithelial p53 gene inactivation in the fallopian tube, supporting a multi-hit model of serous carcinogenesis.

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 study demonstrates that polymorphisms in the p53 pathway genes HDM2 and TP53 are associated with accelerated decline in lung function in cigarette smokers. The HDM2 rs2279744 G-allele (associated with reduced p53 response) and TP53 rs1042522 G-allele (encoding p53 R72, promoting apoptosis) were significantly associated with greater smoking-related lung function decline in a longitudinal cohort study of young adults aged 18-32 years (n=668 for HDM2, n=668 for TP53 analysis). The combination of both risk alleles showed a dose-dependent effect on FEV1 decline.

Case-control study of 614 colorectal cancer patients and 614 matched controls in the Czech Republic examining TP53, CDKN1A, and CDKN2A polymorphisms. While individual SNPs showed no associations, TP53 haplotype analysis revealed significant results (global P<0.0001), with the A(2)CCG haplotype showing increased risk (OR=1.40) and five other haplotypes showing decreased risk.

In 57 patients with advanced gastric cancer treated with paclitaxel and cisplatin, the TP53 codon 72 polymorphism (rs1042522) was found to predict chemotherapy response and progression-free survival. Patients carrying Arg/Pro or Pro/Pro genotypes had significantly lower chemotherapy response rates (35.7% vs 66.7%, P=0.019) and worse time to progression (HR=3.056, P=0.047) compared to Arg/Arg carriers.

This study analyzed 15 apoptosis-related gene polymorphisms in 76 patients with metastatic colorectal cancer treated with capecitabine and oxaliplatin chemotherapy. The PTGS2 8473T>C (rs5275) polymorphism was found to be significantly associated with progression-free survival (p=0.038, HR=2.19, dominant model p=0.046) and overall survival (p=0.040, dominant model p=0.013) in multivariate Cox regression analysis.

A case-control study of 70 Caucasian breast cancer patients examined 8 germline polymorphisms in genes involved in oxidative stress protection, apoptosis, and DNA repair (TP53, NQO1, IL6, TLR4, XRCC1) to predict response to neoadjuvant anthracycline-based chemotherapy. Good pathological response (pCR or residual isolated invasive tumor cells) was significantly more frequent in ER/PR-negative tumors (43.5% vs 10.3% in ER/PR-positive, p=0.006) and G3 tumors (42.4% vs 6.3% in G1/G2, p=0.002). A non-significant trend toward good response was observed in TP53 Arg72Pro carriers (Arg/Arg or Arg/Pro) versus Pro/Pro homozygotes (37.9% or 17.6% vs 0%, p=0.071), and XRCC1 Arg194Trp heterozygotes showed decreased overall survival (HR=6.649, p=0.041).

This case-control and family-based association study evaluated 21 TP53 variants and 1 MDM2 variant (rs2279744) in 549 Irish NTD cases, 532 mothers, 481 fathers, and 999 controls. Three TP53 noncoding variants showed associations with neural tube defect risk: rs1625895 (intron 6, GG genotype, OR=1.37, p=0.02), the intron 1 VNTR (135/135 genotype, maternal effect, OR=1.86, p=0.01), and rs1614984 (maternal TT genotype, RR=0.58, p=0.02). However, these associations did not remain significant after multiple testing correction. The functional R72P variant (rs1042522) showed no association with NTD risk.

A systematic review and meta-analysis of 161 published meta-analyses evaluating 344 gene-variant/cancer associations across 99 genes and 18 cancer sites. The authors calculated false-positive report probability (FPRP) values to evaluate the robustness of statistically significant findings (p<0.05). The most noteworthy associations at very low prior probability were GSTM1 null with bladder cancer (OR: 1.5, p=1.9×10-14), NAT2 slow acetylator with bladder cancer (OR: 1.46, p=2.5×10-7), MTHFR C677T with gastric cancer (OR: 1.52, p=4.9×10-8), and GSTM1 null with acute leukemia (OR: 1.20, p=8.6×10-15). Phase II metabolizing enzymes, particularly GSTM1 deletion, showed the most consistent and highly significant associations with cancer risk.

Meta-analysis of 5 case-control studies (567 cases, 935 controls) examining the association between TP53 rs1042522 polymorphism and malignant bone tumor risk. The G allele was significantly associated with increased risk of malignant bone tumors (OR=1.27, 95% CI 1.08-1.50, p=0.005) and the GG genotype showed elevated risk in recessive model (OR=1.55, 95% CI 1.21-2.00, p=0.001), particularly for osteosarcoma.

Case-control study of 731 Norwegian and 1,995 Polish breast cancer cases with 1,124 and 2,296 controls respectively, investigating common genetic variation in TP53 and flanking genes WDR79 and ATP1B2. No significant overall TP53 SNP associations with breast cancer risk were found, but WDR79 rs2287499 (R68G) showed increased risk (OR=1.60 for GG vs CC, p-trend=0.01). Notably, rs2287499 and rs17887200 (TP53) were associated specifically with ER-negative breast cancers (OR=1.42 and 1.48 respectively, p-trend<0.01), but not ER-positive tumors.

Meta-analysis of 51 case-control studies (25,366 cases, 25,239 controls) examining TP53 rs1042522 and MDM2 rs2279744 polymorphisms with lung cancer risk. TP53 rs1042522 showed significant association with lung cancer susceptibility (OR = 0.82, 95% CI 0.71-0.94, p = 0.005 under allelic model) in both Asian and Caucasian populations, while MDM2 rs2279744 showed no significant association.