Li Jiaoyuan, Zou Li, Zhou Ying, Li Lu, Zhu Ying, Yang Yang, Gong Yajie, Lou Jiao, Ke Juntao, Zhang Yi, Tian Jianbo, Zou Danyi, Peng Xiating, Chang Jiang, Gong Jing, Zhong Rong, Zhou Xiaobo, Miao Xiaoping
Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Key Laboratory of Environment and Health, Tongji Medical College, Huazhong University of Science and Technology, Ministry of Education & Ministry of Environmental Protection, Wuhan, China.
Mol Carcinog. 2017 Jul;56(7):1798-1807. doi: 10.1002/mc.22637. Epub 2017 Mar 6.
The TGF-β pathway plays an essential role in regulating cell proliferation and differentiation. GWASs and candidate approaches have identified a battery of genetic variants in the TGF-β pathway contributing to colorectal cancer (CRC). However, most of the significant variants are common variants and their functions remain ambiguous. To identify causal variants with low-frequency in the TGF-β pathway contributing to CRC susceptibility in Chinese population, we performed targeted sequencing of 12 key genes in TGF-β signaling in CRC patients followed by a two-stage case-control study with a total of 5109 cases and 5169 controls. Bioinformatic annotations and biochemical experiments were applied to reveal the potential functions of significant variants. Seven low-frequency genetic variants were captured through targeted sequencing. The two stage association studies showed that missense variant rs3764482 (c. 83C>T; p. S28F) in the gene SMAD7 was consistently and significantly associated with CRC risk. Compared with the wild type, the ORs for variant allele were 1.37 (95%CI: 1.10-1.70, P = 0.005), 1.55 (95%CI: 1.30-1.86, P = 1.15 × 10 ), and 1.48 (1.29-1.70, P = 2.44 × 10 ) in stage 1, stage 2, and the combined analyses, respectively. Functional annotations revealed that the minor allele T of rs3764482 was more effective than the major allele C in blocking the TGF-β signaling and inhibiting the phosphorylation of receptor-regulated SMADs (R-SMADs). In conclusion, low-frequency coding variant rs3764482 in SMAD7 is associated with CRC risk in Chinese population. The rs3764482 variant may block the TGF-β signaling via impeding the activation of downstream genes, leading to cancer cell proliferation, thus contributing to CRC pathogenesis.
转化生长因子-β（TGF-β）信号通路在调节细胞增殖和分化中起着至关重要的作用。全基因组关联研究（GWASs）和候选基因方法已在TGF-β信号通路中鉴定出一系列导致结直肠癌（CRC）的遗传变异。然而，大多数显著变异都是常见变异，其功能仍不明确。为了在中国人群中鉴定TGF-β信号通路中导致CRC易感性的低频因果变异，我们对CRC患者TGF-β信号传导中的12个关键基因进行了靶向测序，随后进行了一项两阶段病例对照研究，共纳入5109例病例和5169例对照。应用生物信息学注释和生化实验来揭示显著变异的潜在功能。通过靶向测序捕获了7个低频遗传变异。两阶段关联研究表明，SMAD7基因中的错义变异rs3764482（c.83C>T；p.S28F）与CRC风险始终显著相关。与野生型相比，在第一阶段、第二阶段和联合分析中，变异等位基因的比值比（OR）分别为1.37（95%置信区间：1.10 - 1.70，P = 0.005）、1.55（95%置信区间：1.30 - 1.86，P = 1.15×10）和1.48（1.29 - 1.70，P = 2.44×10）。功能注释显示，rs3764482的次要等位基因T在阻断TGF-β信号传导和抑制受体调节型SMADs（R - SMADs）磷酸化方面比主要等位基因C更有效。总之，SMAD7基因中的低频编码变异rs3764482与中国人群的CRC风险相关。rs3764482变异可能通过阻碍下游基因的激活来阻断TGF-β信号传导，导致癌细胞增殖，从而促进CRC的发病机制。
