rs4977756

This study investigated the association of MGMT enhancer variant rs11016629 with glioma susceptibility and progression in 402 patients and 654 controls. The TG genotype was associated with increased glioma risk (OR=1.41, 95% CI 1.03-1.93, P=0.034), particularly in WHO grade IV tumors (OR=1.59, P=0.023). In patients who underwent gross total resection, carriers with TG/TT genotypes had worse progression-free survival (HR=2.66, 95% CI 1.23-5.79, P=0.014) compared to GG carriers.

A meta-analysis of 16 studies (8,129 cases, 15,858 controls) examined the association between CDKN2A/B rs4977756 polymorphism and glioma risk. The G allele was associated with increased glioma risk across multiple inheritance models in Caucasians (dominant model: OR=1.36, 95% CI=1.20-1.54; homozygous GG: OR=1.49, 95% CI=1.36-1.64), but no association was found in Asian populations. Results support rs4977756 as a glioma susceptibility locus, particularly in European ancestry populations.

Genome-wide association study and meta-analysis of intraocular pressure (IOP) in 6,236 European ancestry subjects from three cohorts (NEIGHBOR, GLAUGEN, AMD-MMAP MI). Meta-analysis identified a significant association at TMCO1 (rs7518099-G, beta = 0.76 mmHg/allele, p = 8.0 × 10−8). The study replicated previously reported associations at TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6 loci with consistent effect sizes and directions. Results show gender-specific effects and age-dependent trends for IOP association with common variants.

A case-control study examining seven known glioma risk loci in individuals with a family history of brain tumours (104 FHBT-glioma cases, 2,868 controls). Three SNPs were associated with glioma risk: rs2736100 (TERT; OR=1.41, 95% CI 1.05-1.89), rs4977756 (CDKN2A-CDKN2B; OR=2.01, p=0.01), and rs6010620 (RTEL1; OR=0.51, p=0.012 for glioblastoma). Only rs6010620 remained significant after correction for multiple comparisons.

Large pooled case-control study of 49,608 breast cancer cases and 48,772 controls from 39 studies in the Breast Cancer Association Consortium independently confirmed four SNPs as breast cancer susceptibility loci. SNP rs614367 (CCND1 region) showed the strongest association (OR 1.21, P < 1×10⁻⁸) overall and OR 1.29 for hormone receptor-positive breast cancer. SNPs rs1011970 (CDKN2A/2B, OR 1.09), rs10995190 (ZNF365, OR 0.92), and rs704010 (ZMIZ1) were also significantly associated with breast cancer risk in women of European descent, while rs2380205 (10p15) showed limited evidence.

Genome-wide association study of glioma in 1,856 cases and 4,955 controls that confirmed seven previously reported susceptibility loci. Strong replication was found for rs2736100 (TERT, OR=0.72), rs4977756 (CDKN2BAS, OR=1.35), and rs6010620 (RTEL1, OR=0.66). Consistent associations were observed for loci at EGFR, CCDC26, and PHLDB1. Meta-analysis of 85 candidate loci in 5,015 cases and 11,601 controls identified no novel genome-wide significant associations, suggesting glioma genetic architecture may involve fewer common variants than other cancers.

This review discusses recent genome-wide association studies (GWAS) that identified five susceptibility loci for glioma: TERT rs2736100 (OR=1.27), CCDC26 rs4295627 (OR=1.36), CDKN2A/CDKN2B rs4977756 (OR=1.24), RTEL1 rs6010620 (OR=1.18), and PHLDB1 rs498872 (OR=1.28). The combined effect shows that individuals with 8 or more risk alleles have over 3-fold increased glioma risk compared to those with median alleles (OR=1.31 per allele, p=1.39×10^-74). These common low-risk variants represent the strongest evidence to date for inherited susceptibility to glioma, with shared associations across multiple cancer types.