Elucidation of Genetic Susceptibility in Nasopharyngeal Carcinoma by Next Generation Sequencing

Abstract

Background: NPC has a striking geographical distribution. Hong Kong is one of the endemic regions in Southern China with incidence of 20 per 100,000 in males, 10 times higher than the rest of the world. NPC diagnosis usually occurs 20 years earlier than the other common cancers. Family clustering is often observed in both high- and low-risk regions. The relative risk in first degree relatives of NPC patients is increased from 6-10-fold compared to the general population, suggesting the important role of genetics in NPC development. Previously, we applied a whole-exome sequencing (WES) approach to characterize the germline variants in NPC and identified a novel genetic susceptibility gene MST1R associated with NPC cases having an early onset. This study also discovered several potential candidates involved in DNA repair, immune response, and epigenetic regulation. Aim: We aim to 1) validate MST1R as a genetic susceptibility gene and evaluate the clinical significance of its germline variants in association with survival and 2) to examine the association of the rare deleterious variants of fourteen candidate genes in a larger NPC case-control cohort. Methods: We examined the germline variants in 1224 cases (FH: 271 and sporadic 953) and 1256 age/gender matched Hong Kong (HK) controls by the targeted sequencing approach using Roche NimbleGen SeqCap EZ custom platform. Results: The MST1R rare deleterious variants were significantly associated with NPC, especially in the FH+ cases (OR=2.37, p=0.032). Combined analysis including both discovery (WES) and validation cohorts showed that the MST1R variants clustered at the Sema and tyrosine kinase (TK) domains were associated with NPC, respectively. The controls are intolerant to the rare deleterious variants in the TK domain, suggesting the more severe functional impact of those variants to its function. The sporadic cases with MST1R deleterious variants had disease progression (relapse or metastasis) much earlier than those without variants (n=756, HR=3.0, 95% CI 1.2-7.5, p=0.017). Among another fourteen candidates, multiple loss-of-function (LOF) germline mutations of a critical DNA repair gene, ATM, were identified in the FH+ cases, but not in any of sporadic cases and HK controls. Conclusions: This study confirmed MST1R as a genetic susceptibility gene in NPC. It encodes macrophage-stimulating 1 receptor, which has an important function in innate immunity for maintaining the macrophage hemostasis. The function of this gene and impact of its germline variants in NPC development and progression are under investigation. Our study also highlights the role of a DNA repair gene, ATM, in NPC susceptibility.