SNP rs2853669 potentially elevates the risk of glioblastoma development and leads to worse prognosis when in cis with mutant TERT promoter in a Japanese cohort

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2026
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Abstract
Abstract Background Mutations in the telomerase reverse transcriptase (TERT) promoter region (TPM), particularly C228T and C250T, are common in IDH-wildtype glioblastoma (GBM). The single nucleotide polymorphism (SNP) rs2853669, also located in the TERT promoter, may influence telomerase activity, though its clinical relevance in GBM remains unclear. This study examined the allelic configuration between rs2853669 and TPM to elucidate their combined effects on TERT expression and clinical outcome. Methods Seventy-six TPM-positive GBM tumors from Japanese patients were analyzed by nested PCR, and patients were classified by rs2853669 genotype (T/T, T/C, C/C). In the T/C subgroup, the allelic configuration between the SNP and TPM was determined as cis (same allele) or trans (different alleles). Clinical data, TERT expression, and prognosis were compared among groups. Results Among 76 patients, 37 (48.7%) had T/T, 30 (39.5%) had T/C, and 9 (11.8%) had C/C genotypes. The rs2853669 C allele frequency was higher in GBM than in the general Japanese population (31.6% vs 24.5%, p = 0.047). Among T/C cases, 53.3% showed a cis configuration. Patients carrying the SNP and TPM on the same allele (C/C and T/C cis) had shorter overall survival than those carrying them on different alleles (T/T or T/C trans; 19 vs 25 months, p = 0.048), and TERT expression was also lower in this group (p = 0.038). Conclusion The rs2853669 C allele may increase GBM susceptibility and, when in cis with TPM, is associated with reduced TERT expression and poorer prognosis, underscoring its biological and clinical significance in TPM-mutant GBM.
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Authors Daisuke Kawauchi, Yohei Miyake, Brett Taylor, Joseph Bendik, Shunichiro Miki, Mai Honda‐Kitahara, Jill Barnholtz-Sloan, Tomoyuki Nakano, Philip Pham, Raghavendra Vadla, Brandon M Jones, Clark Wang, Sejal Patel, Yoshitaka Narita, Frank Furnari
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Journal journal of neuro-oncology
Year 2026
DOI
10.1093/neuonc/noag237
URL
https://doi.org/10.1093/neuonc/noag237
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