Guo-Wang Lin1, Caigang Xu2, Kexin Chen3, Hui-Qiang Huang4, Jieping Chen5, Bao Song6, John K C Chan7, Wenyu Li8, Weiping Liu9, Lee-Yung Shih10, Wen-Yu Chuang11, Won Seog Kim12, Wen Tan13, Rou-Jun Peng4, Yurike Laurensia14, Daryl Ming Zhe Cheah14, DaChuan Huang14, Chee Leong Cheng15, Yi-Jiun Su16, Soo-Yong Tan17, Siok-Bian Ng18, Tiffany Pooi Ling Tang19, Kyudong Han20, Vivien Ya-Fan Wang21, Wei-Hua Jia4, Zhong Pei22, Ya-Jun Li23, Song Gao4, Yongyong Shi24, Zhibin Hu25, Furen Zhang26, Ben Zhang27, Yi-Xin Zeng4, Hongbing Shen25, Lin He24, Choon Kiat Ong28, Soon Thye Lim29, Stephen Chanock30, Yok-Lam Kwong31, Dongxin Lin32, Nathaniel Rothman30, Chiea Chuen Khor33, Qing Lan30, Jin-Xin Bei34. 1. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China. 2. Hematology Research Laboratory, Department of Hematology, West China Hospital, Sichuan University, Chengdu, China. 3. Department of Epidemiology and Biostatistics, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China. 4. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China. 5. Department of Hematology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China. 6. Department of Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, Shandong, China. 7. Department of Pathology, Queen Elizabeth Hospital, Hong Kong Special Administrative Region, China. 8. Department of Lymphoma, Guangdong Academy of Medical Sciences, Guangzhou, China. 9. Department of Pathology, West China Hospital, Sichuan University, Chengdu, China. 10. Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan; Chang Gung University, Taoyuan. 11. Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan. 12. Division of Hematology and Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea. 13. Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 14. Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore. 15. Department of Pathology, Singapore General Hospital, Singapore. 16. Division of Hematology-Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan. 17. Department of Pathology, Guangdong Academy of Medical Sciences, Guangzhou, China; Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Department of Pathology, National University Hospital, National University Health System, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore; Department of Pathology, University of Malaya, Kuala Lumpur, Malaysia. 18. Department of Pathology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Pathology, National University Hospital, National University Health System, Singapore. 19. Division of Medical Oncology, National Cancer Centre Singapore, Singapore. 20. Department of Nanobiomedical Science, BK21 PLUS NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, South Korea. 21. Faculty of Health Sciences, University of Macau, Macau Special Administrative Region, China. 22. Department of Neurology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. 23. Department of Lymphoma and Hematology, Hunan Cancer Hospital, Changsha, China; The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China. 24. The Affiliated Hospital of Qingdao University & the Biomedical Sciences Institute of Qingdao University, Qingdao Branch of SJTU Bio-X Institutes, Qingdao University, Qingdao, China; Bio-X Institutes, Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders (Ministry of Education), the Collaborative Innovation Center for Brain Science, Shanghai Jiao Tong University, Shanghai, China; Shanghai Key Laboratory of Sleep Disordered Breathing, Shanghai, China. 25. Department of Epidemiology and Biostatistics, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, China. 26. Shandong Provincial Institute of Dermatology and Venereology, Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan, China. 27. Department of Epidemiology and Biostatistics, First Affiliated Hospital, Army Medical University, Chongqing, China. 28. Lymphoma Genomic Translational Research Laboratory, Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore; Genome Institute of Singapore, Singapore; Duke-NUS Medical School, Singapore. 29. Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Duke-NUS Medical School, Singapore; SingHealth Duke-NUS Blood Cancer Centre, Singapore. 30. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA. 31. Department of Medicine, Queen Mary Hospital, Hong Kong Special Administrative Region, China. 32. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. 33. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Genome Institute of Singapore, Singapore; Singapore Eye Research Institute, Singapore. 34. Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China; Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Center for Precision Medicine, Sun Yat-sen University, Guangzhou, China. Electronic address: beijx@sysucc.org.cn.
Abstract
BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.
BACKGROUND: Extranodal natural killer T-cell lymphoma (NKTCL; nasal type) is an aggressive malignancy with a particularly high prevalence in Asian and Latin American populations. Epstein-Barr virus infection has a role in the pathogenesis of NKTCL, and HLA-DPB1 variants are risk factors for the disease. We aimed to identify additional novel genetic variants affecting risk of NKTCL. METHODS: We did a genome-wide association study of NKTCL in multiple populations from east Asia. We recruited a discovery cohort of 700 cases with NKTCL and 7752 controls without NKTCL of Han Chinese ancestry from 19 centres in southern, central, and northern regions of China, and four independent replication samples including 717 cases and 12 650 controls. Three of these independent samples (451 cases and 5301 controls) were from eight centres in the same regions of southern, central, and northern China, and the fourth (266 cases and 7349 controls) was from 11 centres in Hong Kong, Taiwan, Singapore, and South Korea. All cases had primary NKTCL that was confirmed histopathologically, and matching with controls was based on geographical region and self-reported ancestry. Logistic regression analysis was done independently by geographical regions, followed by fixed-effect meta-analyses, to identify susceptibility loci. Bioinformatic approaches, including expression quantitative trait loci, binding motif and transcriptome analyses, and biological experiments were done to fine-map and explore the functional relevance of genome-wide association loci to the development of NKTCL. FINDINGS: Genetic data were gathered between Jan 1, 2008, and Jan 23, 2019. Meta-analysis of all samples (a total of 1417 cases and 20 402 controls) identified two novel loci significantly associated with NKTCL: IL18RAP on 2q12.1 (rs13015714; p=2·83 × 10-16; odds ratio 1·39 [95% CI 1·28-1·50]) and HLA-DRB1 on 6p21.3 (rs9271588; 9·35 × 10-26 1·53 [1·41-1·65]). Fine-mapping and experimental analyses showed that rs1420106 at the promoter of IL18RAP was highly correlated with rs13015714, and the rs1420106-A risk variant had an upregulatory effect on IL18RAP expression. Cell growth assays in two NKTCL cell lines (YT and SNK-6 cells) showed that knockdown of IL18RAP inhibited cell proliferation by cell cycle arrest in NKTCL cells. Haplotype association analysis showed that haplotype 47F-67I was associated with reduced risk of NKTCL, whereas 47Y-67L was associated with increased risk of NKTCL. These two positions are component parts of the peptide-binding pocket 7 (P7) of the HLA-DR heterodimer, suggesting that these alterations might account for the association at HLA-DRB1, independent of the previously reported HLA-DPB1 variants. INTERPRETATION: Our findings provide new insights into the development of NKTCL by showing the importance of inflammation and immune regulation through the IL18-IL18RAP axis and antigen presentation involving HLA-DRB1, which might help to identify potential therapeutic targets. Taken in combination with additional genetic and other risk factors, our results could potentially be used to stratify people at high risk of NKTCL for targeted prevention. FUNDING: Guangdong Innovative and Entrepreneurial Research Team Program, National Natural Science Foundation of China, National Program for Support of Top-Notch Young Professionals, Chang Jiang Scholars Program, Singapore Ministry of Health's National Medical Research Council, Tanoto Foundation, National Research Foundation Singapore, Chang Gung Memorial Hospital, Recruitment Program for Young Professionals of China, First Affiliated Hospital and Army Medical University, US National Institutes of Health, and US National Cancer Institute.
Authors: Francisco Vega; Catalina Amador; Amy Chadburn; Eric D Hsi; Graham Slack; L Jeffrey Medeiros; Andrew L Feldman Journal: Mod Pathol Date: 2021-09-28 Impact factor: 7.842