Elucidating the Genetic Basis for Early-age Onset Nasopharyngeal Carcinoma in Hong Kong

Abstract

Introduction and project objectives: Nasopharyngeal carcinoma (NPC) is an intriguing cancer of special relevance to Hong Kong, where it is also dubbed the “Guangdong tumor” because of its especially high incidence among the Southern Chinese. The peak age for NPC diagnosis is in the upper 40’s. In Hong Kong, a small proportion of NPC patients are early-age onset (EAO) pediatric patients, who are diagnosed with this cancer at 20 years of age or less and who have a higher frequency of advanced-stage cancers. Very little is known about these patients. The aim of the study is to utilize the whole-exome sequencing (WES) approach to characterize the germline variants of EAO NPC in Hong Kong in to understand the genetic basis for this rare group of NPC patients. Methods: A total of 39 EAO NPC patients were sequenced using Illumina TruSeq WES kit. Additional 63 cases from 52 family historypositive (FH+) NPC families and 59 sporadic cases, and controls including 895 non-cancer Southern Chinese were also studied by WES. The selected variant was validated by LightSNiP assay in 2160 cases and 2433 controls. We further examined the candidate gene using a Roche NimbleGen SeqCap targeted sequencing approach in 1224 NPC cases and 1256 non-cancer controls. Results: Five rare deleterious missense variants at MST1R were identified in the EAO cases by WES, but were rare in the controls (EAO cases vs. controls: 17.95% vs. 1.22%, p=7.94×10-12). The gene-based burden test including WES data from a total of 161 NPC cases and 895 controls confirmed the association between MST1R and NPC (Variant Test p=0.0009). The validation study including 2160 cases and 2433 controls showed that the MST1R variant c.G917A:p.R306H is highly associated with NPC (odds ratio=9.0) [1]. The follow-up validation study for MST1R gene-level targeted sequencing further demonstrated that the NPC cases more frequently carried the rare deleterious variants at this gene, especially in the intracellular domain, than the non-cancer controls (p=0.036). Conclusion: Our study highlights the role of MST1R as a NPC genetic susceptibility gene. MST1R, encoding Macrophage-Stimulating Receptor 1, is predominantly expressed in the tissueresident macrophages and is critical for innate immunity that protects organs from tissue damage and inflammation. Our data suggest that the deleterious germline variants may impair its function in innate immunity and host defense. Reference: [1] Dai W, Zheng H, et al. Lung M. WES Identifies MST1R as a Novel Genetic Susceptibility Gene in NPC. PNAS. 2016