Whole-Exome Sequencing Study of Familial Nasopharyngeal Carcinoma and Its Implication for Identifying High-Risk Individuals

Abstract

Background Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus (EBV) infection, showing significant familial aggregation. Individuals with a family history suffer elevated NPC risk, requiring effective genetic counseling for risk stratification and individualized prevention. Methods We performed whole-exome sequencing on 502 familial NPC patients and 404 unaffected relatives and controls. We systematically evaluated the established cancer predisposition genes and investigated novel NPC susceptibility genes, making comparisons with other 21 familial cancers in the UK biobank (N = 5218). Results Rare pathogenic mutations in the established cancer predisposition genes were observed in familial NPC patients, including ERCC2 (1.39%), TP63 (1.00%), MUTYH (0.80%) and BRCA1 (0.80%). Additionally, six novel susceptibility genes were identified. RAD54L involved in DNA repair pathway together with ERCC2, MUTYH, and BRCA1, showed the highest frequency (4.18%) in familial NPC. Enrichment analysis found mutations in TP63 were enriched in familial NPC, while RAD54L and EML2 were enriched in both NPC and other EBV-associated cancers. Besides rare variants, common variants reported in the studies of sporadic NPC were also associated with familial NPC risk. Individuals in the top quantile of common variant-derived genetic risk score (GRSC) while carrying rare variants exhibited increased NPC risk (OR = 13.47, 95% CI: 6.33–28.68, P = 1.48 × 10–11); males in this risk group showed cumulative lifetime risk of 24.19%, much higher than those in the bottom GRSC quantile and without rare variants (2.04%). Conclusions This study expands the catalog of NPC susceptibility genes and provides the potential for risk stratification of individuals with an NPC family history.

Multigene Panel Sequencing Identifies a Novel Germline Mutation Profile in Male Breast Cancer Patients

“…To the best of our knowledge, we are the first study to demonstrate that germline PVs/LPVs mapping to a gene involved in cellular invasion, PALLD , are represented at an increased prevalence in an MBC cohort compared with a male noncancer NFE and an FBC population. The second gene, ERCC2 , encoding an adenosine triphosphate (ATP)-dependent DNA helicase, is frequently mutated in families with increased nasopharyngeal carcinoma risk [ 43 ]. A polymorphism in this gene (p.Asp312Asn) is associated with bladder, oesophageal, and gastric cancers but not with breast or prostate cancer [ 44 ].…”

Overexpression of RAD54L attenuates osteoarthritis by suppressing the HIF-1α/VEGF signaling pathway: Bioinformatics analysis and experimental validation

“…For example, RAD54L expression levels are significantly correlated with different stages of non-small-cell lung cancer [ 14 ]. RAD54L together with other novel susceptibility genes have been shown the highest frequency in familial nasopharyngeal carcinoma [ 15 ]. In addition, the cell division cycle 7-RAD54L pathway is functionally required for tumorigenicity and radio resistance of glioblastoma [ 16 ].…”

Polygenic risk-stratified screening for nasopharyngeal carcinoma in high-risk endemic areas of China: a cost-effectiveness study

“…This approach has emerged as a promising tool for personalized screening in breast cancers and prostate cancers, and has also demonstrated to improve the costeffectiveness and the benefit-to-harm ratio (14)(15)(16)(17)(18)(19)(20). Given the regional distribution disparities, familial clustering, and high heritability of NPC, genetic factors are believed to play an important role in its etiology (4,(21)(22)(23)(24)(25). This makes NPC an ideal candidate for developing a PRS for risk stratification, especially in high-risk regions of Southern China.…”