Esophageal cancer is the eighth most common and sixth most frequent fatal human cancer in the world, and the fourth most common incident cancer in China. Shanxi Province, a region in north central China, has among the highest esophageal cancer rates in China, and nearly all of these cases are esophageal squamous cell carcinoma (ESCC). Understanding the molecular mechanisms underlying esophageal carcinogenesis and its molecular pathology will facilitate the development of biomarkers for early detection to reduce ESCC mortality. Genome-wide association studies (GWAS) have found many loci associated with the development of ESCC, however, most of the significant SNPs identified by GWAS are noncoding variants with unknown functions located in intergenic regions far from genes and are difficult to study functionally. As an initial effort to identify causal variants for ESCC, we focused here on loci near genes with known biological functions. Our analysis consists of three steps. We identified some functional variants for ESCC in the second and third steps of the analysis. First, from the GWAS analysis we selected those loci in or around the genes in three important pathways - inflammation, immunity, and DNA repair - using information from KEGG, Biocarta, and GO databases. We selected loci which had their 95% confidence intervals of the odds ratios not including OR = 1 based on GWAS analysis. Second, we integrated the expression and genotype data from ESCC somatic and germline samples and computed eQTLs using the normal tissues for n = 100 cases which had both gene expression data and GWAS genotype data. We found some interesting results from the second step analysis. The top 20 most significant genes included XPC, TP73, CASP8, DAPK1, IGF1R and LEPR, which were implicated in different cancers (Cancer Genetics Web: http://www.cancer-genetics.org). CASP8 was known to be involved in apoptosis processes. It was significantly associated with early onset of esophageal adenocarcinoma (Wu et al, Neoplasia. 2011 Apr;13(4):386-92). It had been shown that IGF1R had a key role in malignant progression of esophageal cancer (Kalinina et al, Int J Cancer. 2010 Oct 15;127(8):1931-40; Doyle et al, Am J Gastroenterol. 2012 Feb;107(2):196-204). Finally, we further intersected these significant loci in the eQTL analysis with the loci that had significant association between genotype and the somatic DNA copy number alterations. One of the significant genes was ST6GAL1. It had been reported this gene may promote malignant progression by promoting the TGF-beta induced EMT through down-regulation of E-cadherin-mediated cell adhesion and up-regulation of integrin-mediated cell migration (J. Lu et al, J Biol Chem. 2014 Dec 12;289(50):34627-41). We also found some novel genes in the analyses and their relation to ESCC will be investigated in future.

Citation Format: Howard H. Yang, Hua Su, Huaitian Liu, Nan Hu, Chaoyu Wang, Lemin Wang, Ti Ding, Carol Giffen, Alisa M. Goldstein, Philip R. Taylor, Maxwell P. Lee. Integrated analysis of ESCC tumor/normal tissues and patient blood samples using expression, genotypes and DNA somatic change data. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2561.