Abstract Nasopharyngeal carcinoma (NPC) is a malignant tumor that emerges from the epithelium of the nasopharynx, the upper part of the throat behind the nose. It has remarkable ethnic and geographical distribution. It is extremely common in Southern China including Hong Kong. Multiple factors including host genetics, environmental factors, and Epstein-Barr virus (EBV) infection contribute to NPC pathogenesis. NPC diagnosis usually occurs in people in their upper 40s and early 50s, which is close to 20 years younger than for many of the other common cancers. Familial NPC accounts for about 10% of the cases. The risk of the individuals with first-degree relatives having NPC is dramatically increased compared to those without a family history, strongly suggesting the importance of host genetics in NPC development. Recently, we used the whole-exome sequencing (WES) approach to characterize the genetic variants in the coding regions in the family-history positive (FH+) and early age onset (EAO) NPC patients. Gene-level burden tests suggested a link between multiple deleterious variants at MST1R and NPC risk, particularly in the EAO patients with disease onset at or younger than 201. In addition, we identified multiple rare deleterious variants in a number of candidate genes in at least 5% of the FH+ or EAO cases. To further investigate the role of these potential genetic susceptibility genes, we used a NGS-based targeted sequencing approach to examine the germline rare deleterious variants with minor allele frequency (MAF)<0.001 in 17 genes selected from WES study in 1269 controls and 1242 cases including 334 FH+ and 904 sporadic cases. These genes are involved in DNA repair, immune response, and epigenetic regulator. Both filtering strategy and gene-level burden tests were used to identify the genetic susceptibility genes in NPC. Multiple loss-of-function (LOF) germline mutations of a critical DNA repair gene, ATM, was identified in FH+ cases. This gene plays an important role in the formation of the replication compartment during lytic replication of EBV in nasopharyngeal epithelial cells. In addition, we discovered that the rare deleterious variants of MST1R in the intracellular part may play a role in the pathogenesis in both FH+ and sporadic cases. Our study highlights the importance of innate immunity and DNA repair in NPC genetic susceptibility. Reference: 1. Dai W, Zheng H, Cheung AK, et al. Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma. Proc Natl Acad Sci U S A 2016;113:3317-22. Citation Format: Wei Dai, Hong Zheng, Josephine M.Y. Ko, Arthur K.L. Cheung, Maria Li Lung. Elucidation of genetic susceptibility genes using next-generation sequencing (NGS) approach in nasopharyngeal carcinoma [abstract]. In: Proceedings of the AACR-AHNS Head and Neck Cancer Conference: Optimizing Survival and Quality of Life through Basic, Clinical, and Translational Research; April 23-25, 2017; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(23_Suppl):Abstract nr 14.