Whole-Exome Sequencing Study of Familial Nasopharyngeal Carcinoma and Its Implication for Identifying High-Risk Individuals
Tong‐Min Wang, Yong‐Qiao He, Wen‐Qiong Xue, Jiangbo Zhang, Yunfei Xia, Changmi Deng, Wenli Zhang, Ruowen Xiao, Ying Liao, Da-Wei Yang, Ting Zhou, Dan‐Hua Li, Lu‐Ting Luo, Xia‐Ting Tong, Yanxia Wu, Xue‐Yin Chen, Xi‐Zhao Li, Pei‐Fen Zhang, Xiao‐Hui Zheng, Shaodan Zhang, Ye‐Zhu Hu, Fang Wang, Ziyi Wu, Mei‐Qi Zheng, Jingwen Huang, Yijing Jia, Leilei Yuan, Rui You, Guan‐Qun Zhou, Lixia Lu, Yuying Liu, Ming‐Yuan Chen, Lin Feng, Wei Dai, Zefang Ren, Hai‐Qiang Mai, Ying Sun, Jun Ma, Wei Zheng, Maria Li Lung, Wei‐Hua Jia
Abstract
BACKGROUND: Nasopharyngeal carcinoma (NPC) is closely associated with genetic factors and Epstein-Barr virus infection, showing strong 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 21 other 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, 6 novel susceptibility genes were identified. RAD54L, involved in the 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, and RAD54L and EML2 were enriched in both NPC and other Epstein-Barr virus-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 while carrying rare variants exhibited increased NPC risk (odds ratio = 13.47, 95% confidence interval = 6.33 to 28.68, P = 1.48 × 10-11); men in this risk group showed a cumulative lifetime risk of 24.19%, much higher than those in the bottom common variant-derived genetic risk score 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.