Rare POLN mutations confer risk for familial nasopharyngeal carcinoma through weakened Epstein-Barr virus lytic replication
Summary: Background: Nasopharyngeal carcinoma (NPC) exhibits significant familial aggregation; however, its susceptibility genes are largely unknown. Thus, this study aimed to identify germline mutations that might contribute to the risk of familial NPC, and explore their biological functions. Meth...
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Elsevier
2022-10-01
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| Series: | EBioMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352396422004492 |
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| author | Ruo-Wen Xiao Fang Wang Tong-Min Wang Jiang-Bo Zhang Zi-Yi Wu Chang-Mi Deng Ying Liao Ting Zhou Da-Wei Yang Si-Qi Dong Wen-Qiong Xue Yong-Qiao He Xiao-Hui Zheng Xi-Zhao Li Pei-Fen Zhang Shao-Dan Zhang Ye-Zhu Hu Yu-Ying Liu Yun-Fei Xia Song Gao Jian-Bing Mu Lin Feng Wei-Hua Jia |
| author_facet | Ruo-Wen Xiao Fang Wang Tong-Min Wang Jiang-Bo Zhang Zi-Yi Wu Chang-Mi Deng Ying Liao Ting Zhou Da-Wei Yang Si-Qi Dong Wen-Qiong Xue Yong-Qiao He Xiao-Hui Zheng Xi-Zhao Li Pei-Fen Zhang Shao-Dan Zhang Ye-Zhu Hu Yu-Ying Liu Yun-Fei Xia Song Gao Jian-Bing Mu Lin Feng Wei-Hua Jia |
| author_sort | Ruo-Wen Xiao |
| collection | DOAJ |
| description | Summary: Background: Nasopharyngeal carcinoma (NPC) exhibits significant familial aggregation; however, its susceptibility genes are largely unknown. Thus, this study aimed to identify germline mutations that might contribute to the risk of familial NPC, and explore their biological functions. Methods: Whole-exome sequencing was performed in 13 NPC pedigrees with multiple cases. Mutations co-segregated with disease status were further validated in a cohort composed of 563 probands from independent families, 2,953 sporadic cases, and 3,175 healthy controls. Experimental studies were used to explore the functions of susceptibility genes and their disease-related mutations. Findings: The three rare missense mutations in POLN (DNA polymerase nu) gene, P577L, R303Q, and F545C, were associated with familial NPC risk (5/576 [0·87%] in cases vs. 2/3374 [0·059%] in healthy controls with an adjusted OR of 44·84 [95% CI:3·91-514·34, p = 2·25 × 10−3]). POLN was involved in Epstein-Barr virus (EBV) lytic replication in NPC cells in vitro. POLN promoted viral DNA replication, immediate-early and late lytic gene expression, and progeny viral particle production, ultimately affecting the proliferation of host cells. The three mutations were located in two pivotal functional domains and were predicted to alter the protein stability of POLN in silico. Further assays demonstrated that POLN carrying any of the three mutations displayed reduced protein stability and decreased expression levels, thereby impairing its ability to promote complete EBV lytic replication and facilitate cell survival. Interpretation: We identified a susceptibility gene POLN for familial NPC and elucidated its function. Funding: This study was funded by the National Key Research and Development Program of China (2021YFC2500400); the National Key Research and Development Program of China (2020YFC1316902); the Basic and Applied Basic Research Foundation of Guangdong Province, China (2021B1515420007); the National Natural Science Foundation of China (81973131); the National Natural Science Foundation of China (82003520); the National Natural Science Foundation of China (81903395). |
| first_indexed | 2024-12-10T03:43:44Z |
| format | Article |
| id | doaj.art-d3769cfc1abe4864b27c2bf08e9b9952 |
| institution | Directory Open Access Journal |
| issn | 2352-3964 |
| language | English |
| last_indexed | 2024-12-10T03:43:44Z |
| publishDate | 2022-10-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EBioMedicine |
| spelling | doaj.art-d3769cfc1abe4864b27c2bf08e9b99522022-12-22T02:03:31ZengElsevierEBioMedicine2352-39642022-10-0184104267Rare POLN mutations confer risk for familial nasopharyngeal carcinoma through weakened Epstein-Barr virus lytic replicationRuo-Wen Xiao0Fang Wang1Tong-Min Wang2Jiang-Bo Zhang3Zi-Yi Wu4Chang-Mi Deng5Ying Liao6Ting Zhou7Da-Wei Yang8Si-Qi Dong9Wen-Qiong Xue10Yong-Qiao He11Xiao-Hui Zheng12Xi-Zhao Li13Pei-Fen Zhang14Shao-Dan Zhang15Ye-Zhu Hu16Yu-Ying Liu17Yun-Fei Xia18Song Gao19Jian-Bing Mu20Lin Feng21Wei-Hua Jia22State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Department of Radiation Oncology, Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaGuangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaScreening Center for Cancer Prevention, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaDepartment of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, ChinaLaboratory of Malaria and Vector Research, National Institute of Allergy and Infectious Diseases, National Institute of Health, Rockville, Maryland, USAState Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Corresponding author at: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, BLDG 2, RM903, Guangzhou, Guangdong, PR China. 510060.State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; Corresponding author at: State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, 651 Dongfeng East Road, BLDG 2, RM903, Guangzhou, Guangdong, PR China. 510060.Summary: Background: Nasopharyngeal carcinoma (NPC) exhibits significant familial aggregation; however, its susceptibility genes are largely unknown. Thus, this study aimed to identify germline mutations that might contribute to the risk of familial NPC, and explore their biological functions. Methods: Whole-exome sequencing was performed in 13 NPC pedigrees with multiple cases. Mutations co-segregated with disease status were further validated in a cohort composed of 563 probands from independent families, 2,953 sporadic cases, and 3,175 healthy controls. Experimental studies were used to explore the functions of susceptibility genes and their disease-related mutations. Findings: The three rare missense mutations in POLN (DNA polymerase nu) gene, P577L, R303Q, and F545C, were associated with familial NPC risk (5/576 [0·87%] in cases vs. 2/3374 [0·059%] in healthy controls with an adjusted OR of 44·84 [95% CI:3·91-514·34, p = 2·25 × 10−3]). POLN was involved in Epstein-Barr virus (EBV) lytic replication in NPC cells in vitro. POLN promoted viral DNA replication, immediate-early and late lytic gene expression, and progeny viral particle production, ultimately affecting the proliferation of host cells. The three mutations were located in two pivotal functional domains and were predicted to alter the protein stability of POLN in silico. Further assays demonstrated that POLN carrying any of the three mutations displayed reduced protein stability and decreased expression levels, thereby impairing its ability to promote complete EBV lytic replication and facilitate cell survival. Interpretation: We identified a susceptibility gene POLN for familial NPC and elucidated its function. Funding: This study was funded by the National Key Research and Development Program of China (2021YFC2500400); the National Key Research and Development Program of China (2020YFC1316902); the Basic and Applied Basic Research Foundation of Guangdong Province, China (2021B1515420007); the National Natural Science Foundation of China (81973131); the National Natural Science Foundation of China (82003520); the National Natural Science Foundation of China (81903395).http://www.sciencedirect.com/science/article/pii/S2352396422004492Familial nasopharyngeal carcinomaWhole-exome sequencingPOLN geneRare germline mutationsEpstein-Barr virus |
| spellingShingle | Ruo-Wen Xiao Fang Wang Tong-Min Wang Jiang-Bo Zhang Zi-Yi Wu Chang-Mi Deng Ying Liao Ting Zhou Da-Wei Yang Si-Qi Dong Wen-Qiong Xue Yong-Qiao He Xiao-Hui Zheng Xi-Zhao Li Pei-Fen Zhang Shao-Dan Zhang Ye-Zhu Hu Yu-Ying Liu Yun-Fei Xia Song Gao Jian-Bing Mu Lin Feng Wei-Hua Jia Rare POLN mutations confer risk for familial nasopharyngeal carcinoma through weakened Epstein-Barr virus lytic replication EBioMedicine Familial nasopharyngeal carcinoma Whole-exome sequencing POLN gene Rare germline mutations Epstein-Barr virus |
| title | Rare POLN mutations confer risk for familial nasopharyngeal carcinoma through weakened Epstein-Barr virus lytic replication |
| title_full | Rare POLN mutations confer risk for familial nasopharyngeal carcinoma through weakened Epstein-Barr virus lytic replication |
| title_fullStr | Rare POLN mutations confer risk for familial nasopharyngeal carcinoma through weakened Epstein-Barr virus lytic replication |
| title_full_unstemmed | Rare POLN mutations confer risk for familial nasopharyngeal carcinoma through weakened Epstein-Barr virus lytic replication |
| title_short | Rare POLN mutations confer risk for familial nasopharyngeal carcinoma through weakened Epstein-Barr virus lytic replication |
| title_sort | rare poln mutations confer risk for familial nasopharyngeal carcinoma through weakened epstein barr virus lytic replication |
| topic | Familial nasopharyngeal carcinoma Whole-exome sequencing POLN gene Rare germline mutations Epstein-Barr virus |
| url | http://www.sciencedirect.com/science/article/pii/S2352396422004492 |
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