Department of Epidemiology and Biostatistics, and State Key Laboratory of Environment Health, MOE (Ministry of Education) Key Laboratory of Environment & Health, Ministry of Environmental Protection Key Laboratory of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Department of Laboratory Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cancer Epidemiol Biomarkers Prev. 2018 Sep;27(9):1029-1035. doi: 10.1158/1055-9965.EPI-18-0099. Epub 2018 Jun 11.
Telomere dysfunction triggers cellular senescence and constitutes a driving force for cancer initiation. Genetic variants in genes involved in telomere maintenance may contribute to colorectal cancer susceptibility. In this study, we firstly captured germline mutations in 192 patients with colorectal cancer by sequencing the coding regions of 13 core components implicated in telomere biology. Five potential functional variants were then genotyped and assessed in a case-control set with 3,761 colorectal cancer cases and 3,839 healthy controls. The promising association was replicated in additional 6,765 cases and 6,906 controls. Functional experiments were used to further clarify the potential function of the significant variant and uncover the underlying mechanism in colorectal cancer development. The two-stage association studies showed that a rare missense variant rs149418249 (c.1520 and p.P507L) in the 11th exon of (also known as , gene ID 65057) was significantly associated with colorectal cancer risk with the ORs being 2.90 [95% confidence interval (CI), 1.04-8.07; = 0.041], 2.50 (95% CI, 1.04-6.04; = 0.042), and 2.66 (95% CI, 1.36-5.18; = 0.004) in discovery, replication, and the combined samples, respectively. Further functional annotation indicated that the TPP1 P507L substitution interrupted TPP1-TIN2 interaction, impaired telomerase processivity, and shortened telomere length, which subsequently facilitated cell proliferation and promoted colorectal cancer development. A rare variant P507L in TPP1 confers increased risk of colorectal cancer through interrupting TPP1-TIN2 interaction, impairing telomerase processivity, and shrinking telomere length. These findings emphasize the important role of telomere dysfunction in colorectal cancer development, and provide new insights about the prevention of this type of cancer. .
端粒功能障碍触发细胞衰老，并构成癌症发生的驱动力。涉及端粒维持的基因中的遗传变异可能导致结直肠癌易感性。在这项研究中，我们首先通过对涉及端粒生物学的 13 个核心成分的编码区域进行测序，在 192 名结直肠癌患者中捕获了种系突变。然后对 5 个潜在的功能变体进行基因分型，并在包含 3761 名结直肠癌病例和 3839 名健康对照的病例对照集中进行评估。在另外的 6765 例病例和 6906 例对照中复制了有希望的关联。功能实验用于进一步阐明显着变体的潜在功能，并揭示结直肠癌发展中的潜在机制。两阶段关联研究表明，11 号外显子中的罕见错义变体 rs149418249（c.1520 和 p.P507L）（也称为 ，基因 ID 65057）与结直肠癌风险显着相关，OR 值分别为 2.90 [95%置信区间（CI），1.04-8.07; = 0.041]、2.50（95% CI，1.04-6.04; = 0.042）和 2.66（95% CI，1.36-5.18; = 0.004）在发现、复制和组合样本中。进一步的功能注释表明，TPP1 P507L 取代中断了 TPP1-TIN2 相互作用，损害了端粒酶的连续性，并缩短了端粒长度，随后促进了细胞增殖并促进了结直肠癌的发展。TPP1 中的罕见变体 P507L 通过中断 TPP1-TIN2 相互作用、损害端粒酶连续性和缩短端粒长度，增加了结直肠癌的风险。这些发现强调了端粒功能障碍在结直肠癌发展中的重要作用，并为预防这种类型的癌症提供了新的见解。
