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

Abstract

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, three identified from a pooled analysis of NPC genome-wide association study (GWAS), and one 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 ¼ 1.3 - 10-4), BRD2 (P ¼ 1.6 - 10-3), TNFRSF19 (P ¼ 4.0 - 10-3), and CLPTM1L/TERT (P ¼ 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 ¼ 4.6 - 10-4; for rare variants, P ¼ 0.04). We also observed a suggestive association with rare variants in HNRNPU (P ¼ 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.