Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Mol Carcinog. 2019 Jun;58(6):913-921. doi: 10.1002/mc.22980. Epub 2019 Feb 11.
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 = 7.78 × 10 ), rs10054203 (OR = 1.29, 95%CI: 1.13-1.46, P = 1.37 × 10 ), rs2736107 (OR = 1.28, 95%CI: 1.11-1.47, P = 5.14 × 10 ), 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.
5p15.33 染色体已被报道为肺癌的易感位点。然而，该区域的致病变体尚未完全被揭示。在这项研究中，我们旨在确定与中国人群非小细胞肺癌（NSCLC）易感性相关的功能多态性。对 400 例 NSCLC 病例进行了 5p15.33 区域的靶向测序。我们通过比较基因型频率与 1000 基因组计划的数据，选择候选变体，并在 985 例病例和 970 例对照中验证了它们与 NSCLC 的相关性。在 774 名健康受试者中评估了风险变体与端粒长度的关系。进行了荧光素酶测定和电泳迁移率变动分析（EMSA），以探索潜在功能并揭示致癌机制。结果，我们通过靶向测序鉴定了 1478 个变体，并选择了 17 个候选变体。四个多态性与肺癌风险显著相关，包括 rs7726159（OR=1.34，95%CI：1.18-1.52，P=7.78×10-5），rs10054203（OR=1.29，95%CI：1.13-1.46，P=1.37×10-5），rs2736107（OR=1.28，95%CI：1.11-1.47，P=5.14×10-5）和 rs2853677（OR=1.23，95%CI：1.08-1.39，P=0.002）。rs7726159 和 rs10053203 的次要等位基因与长端粒相关（P=0.008 和 0.036）。从机制上讲，rs7726159-A 通过介导等位基因特异性 MYC 结合来增加 TERT 转录。总之，rs7726159 赋予肺癌易感性的功能变体可能通过影响 MYC 结合并诱导端粒延长来实现，这为端粒生物学在肿瘤发生中的关键作用提供了新的见解。
