Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome-Wide Association Study in Multiple Cohorts.,Advanced Science

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Germline Polymorphisms and Length of Survival of Nasopharyngeal Carcinoma: An Exome-Wide Association Study in Multiple Cohorts.
Advanced Science ( IF 14.3 ) Pub Date : 2020-03-20 , DOI: 10.1002/advs.201903727
Yun-Miao Guo _{1,

2} , Jie-Rong Chen _{1,

3} , Yan-Chun Feng ₁ , Melvin L K Chua _{4,

5} , Yanni Zeng _{1,

6} , Edwin Pun Hui ₇ , Allen K C Chan ₈ , Lin-Quan Tang ₁ , Lin Wang ₁ , Qian Cui ₃ , Hui-Qiong Han ₉ , Chun-Ling Luo ₁ , Guo-Wang Lin ₁ , Yan Liang ₁ , Yang Liu ₁ , Zhong-Lian He ₁ , Yu-Xiang Liu ₁ , Pan-Pan Wei ₁ , Chu-Jun Liu ₁ , Wan Peng ₁ , Bo-Wei Han ₁ , Xiao-Yu Zuo ₁ , Enya H W Ong _{4,

5} , Eugenia L L Yeo _{4,

5} , Kar Perng Low _{4,

5} , Gek San Tan ₁₀ , Tony K H Lim ₁₁ , Jacqueline S G Hwang ₁₁ , Bo Li _{12,

13} , Qi-Sheng Feng ₁ , Xiaojun Xia ₁ , Yun-Fei Xia ₁ , Josephine Ko ₁₄ , Wei Dai ₁₄ , Maria L Lung ₁₄ , Anthony T C Chan ₇ , Dennis Y M Lo ₈ , Mu-Sheng Zeng ₁ , Hai-Qiang Mai ₁ , Jianjun Liu _{3,

15} , Yi-Xin Zeng ₁ , Jin-Xin Bei _{1,

16}

Affiliation

Sun Yat-sen University Cancer Center State Key Laboratory of Oncology in South China Collaborative Innovation Center for Cancer Medicine Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy Guangzhou 510060 P. R. China.
Department of Pathology The Affiliated Hospital of Guangdong Medical University Zhanjiang 524001 P. R. China.
Guangdong Provincial People's Hospital Guangdong Academy of Medical Sciences Guangzhou 510080 P. R. China.
Division of Radiation Oncology and Division of Medical Sciences National Cancer Centre Singapore Singapore 169610 Singapore.
Duke-NUS Medical School Singapore 169857 Singapore.
Faculty of Forensic Medicine Guangdong Province Translational Forensic Medicine Engineering Technology Research Centre Guangdong Province Key Laboratory of Brain Function and Disease Zhongshan School of Medicine Sun Yat-sen University Guangzhou 510080 P. R. China.
Department of Clinical Oncology State Key Laboratory of Translational Oncology Prince of Wales Hospital The Chinese University of Hong Kong Shatin, New Territories Hong Kong SAR P. R. China.
Department of Chemical Pathology Li Ka Shing Institute of Health Sciences State Key Laboratory of Translational Oncology The Chinese University of Hong Kong Shatin, New Territories Hong Kong SAR P. R. China.
Department of Oncology The First Affiliated Hospital of Zhengzhou University Zhengzhou 450052 P. R. China.
Translational Pathology Centre Department of Molecular Pathology Singapore General Hospital Singapore 169856 Singapore.
Department of Anatomical Pathology Singapore General Hospital Singapore 169856 Singapore.
Department of Biochemistry and Molecular Biology Zhongshan School of Medicine Sun Yat-sen University Guangzhou 510080 P. R. China.
RNA Biomedical Institute Sun Yat-sen Memorial Hospital Sun Yat-sen University Guangzhou 510120 P. R. China.
Department of Clinical Oncology University of Hong Kong Pok Fu Lam Hong Kong SAR P. R. China.
Genome Institute of Singapore Genome Building Singapore 138672 Singapore.
Center for Precision Medicine Sun Yat-sen University Guangzhou 510080 P. R. China.

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.

更新日期：2020-03-20

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