Functional polymorphisms on chromosome 5p15.33 disturb telomere biology and confer the risk of non-small cell lung cancer in Chinese population

摘要

The chromosome 5p15.33 has been reported as a susceptibility locus for lung cancer. However, causal variants in this region have not been fully uncovered. In this study, we intended to identify functional polymorphisms associated with non-small cell lung cancer (NSCLC) susceptibility in Chinese population. A targeted sequencing on 5p15.33 region was conducted in 400 NSCLC cases. We selected candidate variants by comparing genotypic frequency with data from 1000 Genomes Project, and their associations with NSCLC were validated in 985 cases and 970 controls. The relationships between risk variants and telomere length were evaluated in 774 healthy subjects. Luciferase assays and electrophoretic mobility shift assays (EMSA) were performed to explore potential functions and reveal carcinogenic mechanisms. As a result, we identified 1478 variants through targeted sequencing and selected 17 candidates. Four polymorphisms exhibited prominent associations with lung cancer risk, including rs7726159 (OR=1.34, 95%CI: 1.18-1.52, P=7.78x10(-6)), rs10054203 (OR=1.29, 95%CI: 1.13-1.46, P=1.37x10(-4)), rs2736107 (OR=1.28, 95%CI: 1.11-1.47, P=5.14x10(-4)), and rs2853677 (OR=1.23, 95%CI: 1.08-1.39, P=0.002). The minor allele of rs7726159 and rs10053203 were associated with long telomeres (P=0.008 and 0.036, respectively). Mechanistically, the rs7726159-A increased TERT transcription through mediating allele-specific MYC binding. In conclusion, the functional variant rs7726159 confers lung cancer susceptibility might by affecting MYC binding and inducing telomere lengthening, which provides a new insight into the crucial role of telomere biology in tumorigenesis.