Background: In China, esophageal cancer is the fourth leading cause of cancer death and essentially all cases are histologically esophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses applied to GWAS data can identify biological pathways and/or groups of genes enriched with disease-associated variants whose individual effect sizes may be too small to be detected by standard single locus methods. Methods: We used the adaptive rank-truncated product (ARTP) method to analyze 1,827 pathways containing 69,420 genes in GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. Pathways were retrieved from five databases: KEGG, BioCarta, Reactome, HumanCys and NCI-Nature curated. Statistical significance was determined by permutation. Results: Associations with ESCC risk (P<0.001) were observed for 60 pathways, which included overlapping pathways from different sources predominantly associated with cell cycle control and signaling, DNA repair, and apoptosis. After excluding genes with previous GWAS hits from the pathway analysis, the KEGG taste transduction pathway and the KEGG metabolic pathways were significantly associated with risk of ESCC (P<0.001). The most significant genes (P<0.001) in these pathways were TAS2R13, TAS2R42, TAS2R14, TAS2R46 and TAS2R50, and MTAP, GAPDH, DCTD, POLD2 and AMDHD1, respectively. Significance: This approach provides new insights into the collective role of genetic variants and ESCC risk in Han Chinese and suggests that genetic alterations associated with taste transduction and metabolic pathways may contribute to cancer susceptibility.

Citation Format: Paula L. Hyland, Han Zhang, Qi Yang, Shih-Wen Lin, Dennis Maeder, Nan Hu, Ze-Zhong Tang, Hua Su, Lemin Wang, Chaoyu Wang, Ti Ding, Jin-Hu Fan, You-Lin Qiao, William Wheeler, Carol Giffen, Laurie Burdett, Zhaoming Wang, Stephen J. Chanock, Sanford M. Dawsey, Neal D. Freedman, Christian C. Abnet, Alisa M. Goldstein, Kai Yu, Philip R. Taylor. Pathway analysis of genome-wide association study data highlights taste transduction and metabolic pathways and esophageal squamous cell carcinoma susceptibility. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2203. doi:10.1158/1538-7445.AM2014-2203