Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome‐Wide Association Study in Multiple Cohorts
Yun‐Miao Guo, Jie‐Rong Chen, Yan‐Chun Feng, Melvin L.K. Chua, Yanni Zeng, Edwin P. Hui, Allen K. C. Chan, Lin‐Quan Tang, Lin Wang, Qian Cui, Huiqiong Han, Chunling Luo, Guo‐Wang Lin, Yan Liang, Yang Liu, Zhonglian He, Yu‐Xiang Liu, Panpan Wei, Chu‐Jun Liu, Peng Wan, Bo‐Wei Han, Xiaoyu Zuo, Enya H.W. Ong, Eugenia L.L. Yeo, Kar Perng Low, Gek San Tan, Tony Kiat Hon Lim, Jacqueline Siok Gek Hwang, Bo Li, Qi‐Sheng Feng, Xiaojun Xia, Yunfei Xia, Josephine Mun Yee Ko, Wei Dai, Maria Li Lung, Anthony T.�C. Chan, Dennis Lo, Mu‐Sheng Zeng, Hai‐Qiang Mai, Jianjun Liu, Yi‐Xin Zeng, Jin‐Xin Bei
Abstract
Abstract Germline polymorphisms are linked with differential survival outcomes in cancers but are not well studied in nasopharyngeal carcinoma (NPC). Here, a two‐phase association study is conducted to discover germline polymorphisms that are associated with the prognosis of NPC. The discovery phase includes two consecutive hospital cohorts of patients with NPC from Southern China. Exome‐wide genotypes at 246 173 single nucleotide polymorphisms (SNPs) are determined, followed by survival analysis for each SNP under Cox proportional hazard regression model. Candidate SNP is replicated in another two independent cohorts from Southern China and Singapore. Meta‐analysis of all samples ( n = 5553) confirms that the presence of rs1131636‐T, located in the 3′‐UTR of RPA1 , confers an inferior overall survival (HR = 1.33, 95% CI = 1.20–1.47, P = 6.31 × 10 −8 ). Bioinformatics and biological assays show that rs1131636 has regulatory effects on upstream RPA1 . Functional studies further demonstrate that RPA1 promotes the growth, invasion, migration, and radioresistance of NPC cells. Additionally, miR‐1253 is identified as a suppressor for RPA1 expression, likely through regulation of its binding affinity to rs1131636 locus. Collectively, these findings provide a promising biomarker aiding in stratifying patients with poor survival, as well as a potential drug target for NPC.