Germline Variants Associated with Nasopharyngeal Carcinoma Predisposition Identified through Whole-Exome Sequencing

SIMPLE SUMMARY: The aim of this study was to identify the germline genetic variants associated with an increased risk of developing nasopharyngeal carcinoma (NPC). DNA samples from 119 Singaporean NPC patients were sequenced, with 17 pathogenic variants in 17 genes found to be enriched in NPC patients as compared to unaffected controls. Five of these variants (in the JAK2, PRDM16, LRP1B, NIN, and NKX2-1 genes) were supported by repeated testing on an independent set of Singaporean NPC patients and unaffected Singaporean controls. A FANCE variant was observed in two siblings with NPC, but not in three unaffected siblings of the same family. Gene-based burden testing recapitulated the association between NKX2-1 and FANCE variants with NPC risk. Pathway analysis revealed a higher frequency of germline mutations in endocytosis and immune-modulating pathways. Our research has identified new variants and genes associated with susceptibility to NPC, which are relevant for an improved understanding of the genetic predisposition of NPC. ABSTRACT: The current understanding of genetic susceptibility factors for nasopharyngeal carcinoma (NPC) is still incomplete. To identify novel germline variants associated with NPC predisposition, we analysed whole-exome sequencing data from 119 NPC patients from Singapore with a family history of NPC and/or with early-onset NPC, together with 1337 Singaporean participants without NPC. Variants were prioritised and filtered by selecting variants with minor allele frequencies of <1% in both local control (n = 1337) and gnomAD non-cancer (EAS) (n = 9626) cohorts and a high pathogenicity prediction (CADD score > 20). Using single-variant testing, we identified 17 rare pathogenic variants in 17 genes that were associated with NPC. Consistent evidence of enrichment in NPC patients was observed for five of these variants (in JAK2, PRDM16, LRP1B, NIN, and NKX2-1) from an independent case-control comparison of 156 NPC patients and 9770 unaffected individuals. In a family with five siblings, a FANCE variant (p. P445S) was detected in two affected members, but not in three unaffected members. Gene-based burden testing recapitulated variants in NKX2-1 and FANCE as being associated with NPC risk. Using pathway analysis, endocytosis and immune-modulating pathways were found to be enriched for mutation burden. This study has identified NPC-predisposing variants and genes which could shed new insights into the genetic predisposition of NPC.