Whole-exome sequencing identifies genetic susceptibility locus associated with familial nasopharyngeal carcinoma

Abstract

Introduction: Nasopharyngeal carcinoma (NPC) has a remarkable ethnic and geographical distribution. In most regions of the world, the incidence rates of NPC for both males and females are <1/100,000 person-years. Dramatically elevated incidence of NPC is observed in the Cantonese population of Southern China including Hong Kong, where incidence of NPC in males has been reported to be 20/100,000 person-years. Familial clustering of NPC is often observed in the Chinese population and other populations. It is reported that the risk of the individuals with first-degree relatives of NPC is dramatically increased by 4-10 fold, compared to those without family history of NPC. Methods: To identify genetic susceptibility genes for NPC, a whole-exome sequencing (WES) study was performed in 161 NPC cases and 895 controls of Southern Chinese descent. Results: Using gene-based burden tests, we found that multiple deleterious (damaging missense and frameshift INDEL) variants from macrophage-stimulating 1 receptor (MST1R) were associated with early-disease onset in NPC [1]. We further performed a single variant association test using the WES data and identified a potential candidate locus at the URT region of Adhesion G Protein-Coupled Receptor 5 (ADGRG5) significantly associated with NPC, particularly in the familial cases (p=1.07x10-6). Out of 9 families with multiple NPC cases sequenced in our study, five families carried this genetic susceptibility variant. We examined this locus using a high throughput LightSNiP assay in a validation cohort including 1935 cases and 1849 controls to confirm its association with NPC (p=0.01, OR=2.54). Conclusions: Host genetics play an important role in NPC development. Besides the genetic variants in the coding region, the variants located in the regulatory region are also important for NPC genetic susceptibility. Validation of other potential candidates from the gene-based and single variant association tests is currently underway. Reference [1] Dai W, Zheng H, Cheung AKL, Tang CSM, Ko JMY, Wong BWY, Leong MML, Sham PC, Cheung F, Kwong DLW, Ngan RKC, Ng WT et al. Whole-Exome Sequencing Identifies MST1R as a Novel Genetic Susceptibility Gene in NPC. PNAS. 2016 Mar 7. Acknowledgement: RGC AoE program grant (AoE/M-06/08 ) to MLL