近日，中国医学科学院北京协和医学院肿瘤医院肿瘤研究所林东昕小组，通过全基因组关联分析，鉴别出多个中国人群食管鳞状细胞癌易感基因位点，并分析了相关基因与环境的互作关系。相关论文日前在线发表于《自然—遗传学》。
作为世界十大常见癌症之一，食管鳞状细胞癌具有明显的地区差异性，且中国具有较高的发生率。以往研究指出的一些潜在食管鳞状细胞癌易感基因变异主要与酒精代谢有关。另外，科学家通过对欧洲人和日本人样本进行全基因组关联分析，发现ADH和/或ALDH2的变异与患食管鳞状细胞癌的风险有关，同时也发现这些基因与酒精有互作关系。
在此次研究中，研究人员对10123例食管鳞状细胞癌患者样本进行了全基因组关联分析和全基因组的基因—环境互作分析。同时，他们将10664例非患者样本作为对照，也进行了相同的分析，结果发现了9个新的食管鳞状细胞癌易感基因位点，其中7个具有显著的边际效应，2个只在基因与饮酒互作中具显著相关性。包括ADH基因簇在内的染色体4q23上的变异位点，在与食管鳞状细胞癌风险相关性中，每一个位点与酒精都具有显著的互作。由此，研究人员进一步综合分析指出，带有ADH1B和ALDH2等位基因的饮酒者，比不带有此等位基因的饮酒者患食管鳞状细胞癌的风险高出4倍。
业内专家认为，该研究阐明了遗传基因对患食管鳞状细胞癌风险的直接影响，也指出饮酒情况下遗传基因对患食管鳞状细胞癌风险的影响。新发现的9个中国人食管鳞状细胞癌易感基因位点，加深了研究人员对该疾病遗传病源的认识，并为下一步遗传图谱和基因功能的研究奠定了基础。此外，酒精代谢途径中所鉴定的风险变异，对于排查食管鳞状细胞癌高风险的中国人群也颇具益处。
该研究工作得到了国家“863”计划、“973”计划、国家自然科学基金委员会以及美国国立卫生研究院的资助。
Genome-wide association analyses of esophageal squamous cell carcinoma in Chinese identify multiple susceptibility loci and gene-environment interactions
Chen Wu, Peter Kraft, Kan Zhai, Jiang Chang, Zhaoming Wang, Yun Li, Zhibin Hu, Zhonghu He, Weihua Jia, Christian C Abnet, Liming Liang, Nan Hu, Xiaoping Miao, Yifeng Zhou, Zhihua Liu, Qimin Zhan, Yu Liu, Yan Qiao, Yuling Zhou, Guangfu Jin, Chuanhai Guo, Changdong Lu, Haijun Yang, Jianhua Fu, Dianke Yu
We conducted a genome-wide association study (GWAS) and a genome-wide gene-environment interaction analysis of esophageal squamous-cell carcinoma (ESCC) in 2,031 affected individuals (cases) and 2,044 controls with independent validation in 8,092 cases and 8,620 controls. We identified nine new ESCC susceptibility loci, of which seven, at chromosomes 4q23, 16q12.1, 17q21, 22q12, 3q27, 17p13 and 18p11, had a significant marginal effect (P = 1.78 × 10−39 to P = 2.49 × 10−11) and two of which, at 2q22 and 13q33, had a significant association only in the gene–alcohol drinking interaction (gene-environment interaction P (PG × E) = 4.39 × 10−11 and PG × E = 4.80 × 10−8, respectively). Variants at the 4q23 locus, which includes the ADH cluster, each had a significant interaction with alcohol drinking in their association with ESCC risk (PG × E = 2.54 × 10−7 to PG × E = 3.23 × 10−2). We confirmed the known association of the ALDH2 locus on 12q24 to ESCC, and a joint analysis showed that drinkers with both of the ADH1B and ALDH2 risk alleles had a fourfold increased risk for ESCC compared to drinkers without these risk alleles. Our results underscore the direct genetic contribution to ESCC risk, as well as the genetic contribution to ESCC through interaction with alcohol consumption.
