Evaluation of rare and common variants from suspected familial or sporadic nasopharyngeal carcinoma (NPC) susceptibility genes in sporadic NPC

Background:Genetic susceptibility is associated with nasopharyngeal carcinoma (NPC). We previously identified rare variants potentially involved in familial NPC and common variants significantly associated with sporadic NPC. Methods:We conducted targeted gene sequencing of 20 genes (16 identified from the study of multiplex families, 3 identified from a pooled analysis of NPC genome wide association study [GWAS], and 1 identified from both studies) among 819 NPC cases and 938 controls from two case-control studies in Taiwan (independent from previous studies). A targeted, multiplex PCR primer panel was designed using the custom Ion AmpliSeq Designer v4.2 targeting the regions of the selected genes. Gene-based and single-variant tests were conducted. Results:We found that NPC was associated with combined common and rare variants in CDKN2A/2B (P=1.3× 10-4), BRD2 (P=1.6 × 10-3), TNFRSF19 (P=4.0 × 10-3) and CLPTM1L/TERT (P=5.4 × 10-3). Such associations were likely driven by common variants within these genes, based on gene-based analyses evaluating common variants and rare variants separately (e.g. for common variants of CDKN2A/2B, P=4.6 × 10-4; for rare variants, P=0.04). We also observed a suggestive association with rare variants in HNRNPU (P=3.8 × 10-3) for NPC risk. In addition, we validated four previously reported NPC-risk associated SNPs. Conclusions:Our findings confirm previously reported associated variants and suggest that some common variants in genes previously linked to familial NPC are associated with the development of sporadic NPC. Impact:NPC-associated genes, including CLPTM1L/TERT, BRD2, and HNRNPU, suggest a role for telomere length maintenance in NPC etiology.