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Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations

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 aime... Full description

Journal Title: The lancet oncology 2020-02, Vol.21 (2), p.306-316
Main Author: Lin, Guo-Wang
Other Authors: Xu, Caigang , Chen, Jieping , Chan, John K C , Li, Wenyu , Liu, Weiping , Shih, Lee-Yung , Kim, Won Seog , Tan, Wen , Peng, Rou-Jun , Cheah, Daryl Ming Zhe , Huang, DaChuan , Cheng, Chee Leong , Su, Yi-Jiun , Tan, Soo-Yong , Wang, Vivien Ya-Fan , Jia, Wei-Hua , Li, Ya-Jun , Gao, Song , Hu, Zhibin , Zhang, Furen , Zeng, Yi-Xin , Shen, Hongbing , He, Lin , Ong, Choon Kiat , Chanock, Stephen , Rothman, Nathaniel , Khor, Chiea Chuen , Bei, Jin-Xin , Chiu, Brian , Li, Zheng , LAM, Tai Hing , Xu, Jun , Ip, Dennis Kai Ming , Li, Gandi , Xu, Gang , Wang, Xiaodong , Bai, Ou , Cai, Qing-Qing , Xia, Yi , Chen, Jie-Rong , Luo, Chun-Ling , Zeng, Yanni , Wei, Pan-Pan , Liu, Chu-Jun , Liu, Yu-Xiang , Cao, Yu-Lu , He, Shuai , Liu, Yang , Ha, Jeslin Chian Hung , Khoo, Lay Poh , Kee, Rebecca Xiangpin , Liu, Yanhui , Zhang, Fen , Chng, Wee Joo , Chan, Jason Yong Sheng , Somasundaram, Nagavalli D/O , Ras, Mohamad Farid Bin Harunal , Yeoh, Kheng-Wei , Goh, Yeow Tee , Grigoropoulos, Nicholas Francis , Wong, Esther Kam Yin , Pang, Jane Wan Lu , Chia, Burton Kuan Hui , Kim, Seok Jin , Yoon, Sang Eun , Kuo, Ching-Yuan , Chen, Tsai-Yun , Huang, Wen-Tsung , Lee, Ming-Yang , Ngan, Kai-Cheong , Liu, Herman , Yip, Sze-Fai , Liu, Jie , Li, Jianyong , Rabkin, Charles S , Berndt, Sonja , Bassig, Bryan , Hu, Wei , Li, Yuming , Zhai, Qiongli , Shao, Zonghong , Qiu, Lugui , Xu, Shuangnian , Huang, Zhen , Zhong, Shilong , Zhang, Yan , Wang, Xin , Foo, Jia Nee , Dai, Juncheng , Sun, Liangdan , Wang, Zhenzhen , Liu, Hong , Zhou, Hui , Heng, Chew-Kiat , Hong, Chew Soo , Ahn, Jeeyun , Tin, Aung , Li, Bo , Yu, Xueqing
Format: Electronic Article Electronic Article
Language: English
Subjects:
DNA
Quelle: Alma/SFX Local Collection
Publisher: England: Elsevier Ltd
ID: ISSN: 1470-2045
Link: https://www.ncbi.nlm.nih.gov/pubmed/31879220
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title: Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations
format: Article
creator:
  • Lin, Guo-Wang
  • Xu, Caigang
  • Chen, Jieping
  • Chan, John K C
  • Li, Wenyu
  • Liu, Weiping
  • Shih, Lee-Yung
  • Kim, Won Seog
  • Tan, Wen
  • Peng, Rou-Jun
  • Cheah, Daryl Ming Zhe
  • Huang, DaChuan
  • Cheng, Chee Leong
  • Su, Yi-Jiun
  • Tan, Soo-Yong
  • Wang, Vivien Ya-Fan
  • Jia, Wei-Hua
  • Li, Ya-Jun
  • Gao, Song
  • Hu, Zhibin
  • Zhang, Furen
  • Zeng, Yi-Xin
  • Shen, Hongbing
  • He, Lin
  • Ong, Choon Kiat
  • Chanock, Stephen
  • Rothman, Nathaniel
  • Khor, Chiea Chuen
  • Bei, Jin-Xin
  • Chiu, Brian
  • Li, Zheng
  • LAM, Tai Hing
  • Xu, Jun
  • Ip, Dennis Kai Ming
  • Li, Gandi
  • Xu, Gang
  • Wang, Xiaodong
  • Bai, Ou
  • Cai, Qing-Qing
  • Xia, Yi
  • Chen, Jie-Rong
  • Luo, Chun-Ling
  • Zeng, Yanni
  • Wei, Pan-Pan
  • Liu, Chu-Jun
  • Liu, Yu-Xiang
  • Cao, Yu-Lu
  • He, Shuai
  • Liu, Yang
  • Ha, Jeslin Chian Hung
  • Khoo, Lay Poh
  • Kee, Rebecca Xiangpin
  • Liu, Yanhui
  • Zhang, Fen
  • Chng, Wee Joo
  • Chan, Jason Yong Sheng
  • Somasundaram, Nagavalli D/O
  • Ras, Mohamad Farid Bin Harunal
  • Yeoh, Kheng-Wei
  • Goh, Yeow Tee
  • Grigoropoulos, Nicholas Francis
  • Wong, Esther Kam Yin
  • Pang, Jane Wan Lu
  • Chia, Burton Kuan Hui
  • Kim, Seok Jin
  • Yoon, Sang Eun
  • Kuo, Ching-Yuan
  • Chen, Tsai-Yun
  • Huang, Wen-Tsung
  • Lee, Ming-Yang
  • Ngan, Kai-Cheong
  • Liu, Herman
  • Yip, Sze-Fai
  • Liu, Jie
  • Li, Jianyong
  • Rabkin, Charles S
  • Berndt, Sonja
  • Bassig, Bryan
  • Hu, Wei
  • Li, Yuming
  • Zhai, Qiongli
  • Shao, Zonghong
  • Qiu, Lugui
  • Xu, Shuangnian
  • Huang, Zhen
  • Zhong, Shilong
  • Zhang, Yan
  • Wang, Xin
  • Foo, Jia Nee
  • Dai, Juncheng
  • Sun, Liangdan
  • Wang, Zhenzhen
  • Liu, Hong
  • Zhou, Hui
  • Heng, Chew-Kiat
  • Hong, Chew Soo
  • Ahn, Jeeyun
  • Tin, Aung
  • Li, Bo
  • Yu, Xueqing
subjects:
  • Antigen presentation
  • Arrays
  • Association analysis
  • Binding sites
  • Biopsy
  • Cancer
  • Cell cycle
  • Cell proliferation
  • Deoxyribonucleic acid
  • DNA
  • Drb1 protein
  • Epstein-Barr virus
  • Gene expression
  • Gene mapping
  • Genes
  • Genetic aspects
  • Genetic research
  • Genetic variance
  • Genome-wide association studies
  • Genomes
  • Genomics
  • Histocompatibility antigen HLA
  • Immunoregulation
  • Infections
  • Interleukin 1
  • Interleukin 18
  • Lymphocytes T
  • Lymphoma
  • Lymphomas
  • Malignancy
  • Medical research
  • Mutation
  • Natural killer cells
  • Population studies
  • Principal components analysis
  • Quality control
  • Quantitative trait loci
  • Risk factors
  • Studies
  • T cells
  • T-cell lymphoma
  • Therapeutic applications
  • Tumorigenesis
ispartof: The lancet oncology, 2020-02, Vol.21 (2), p.306-316
description: 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. 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. 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 peptid
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 1470-2045
fulltext: fulltext
issn:
  • 1470-2045
  • 1474-5488
url: Link


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titleGenetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations
sourceAlma/SFX Local Collection
creatorLin, Guo-Wang ; Xu, Caigang ; Chen, Jieping ; Chan, John K C ; Li, Wenyu ; Liu, Weiping ; Shih, Lee-Yung ; Kim, Won Seog ; Tan, Wen ; Peng, Rou-Jun ; Cheah, Daryl Ming Zhe ; Huang, DaChuan ; Cheng, Chee Leong ; Su, Yi-Jiun ; Tan, Soo-Yong ; Wang, Vivien Ya-Fan ; Jia, Wei-Hua ; Li, Ya-Jun ; Gao, Song ; Hu, Zhibin ; Zhang, Furen ; Zeng, Yi-Xin ; Shen, Hongbing ; He, Lin ; Ong, Choon Kiat ; Chanock, Stephen ; Rothman, Nathaniel ; Khor, Chiea Chuen ; Bei, Jin-Xin ; Chiu, Brian ; Li, Zheng ; LAM, Tai Hing ; Xu, Jun ; Ip, Dennis Kai Ming ; Li, Gandi ; Xu, Gang ; Wang, Xiaodong ; Bai, Ou ; Cai, Qing-Qing ; Xia, Yi ; Chen, Jie-Rong ; Luo, Chun-Ling ; Zeng, Yanni ; Wei, Pan-Pan ; Liu, Chu-Jun ; Liu, Yu-Xiang ; Cao, Yu-Lu ; He, Shuai ; Liu, Yang ; Ha, Jeslin Chian Hung ; Khoo, Lay Poh ; Kee, Rebecca Xiangpin ; Liu, Yanhui ; Zhang, Fen ; Chng, Wee Joo ; Chan, Jason Yong Sheng ; Somasundaram, Nagavalli D/O ; Ras, Mohamad Farid Bin Harunal ; Yeoh, Kheng-Wei ; Goh, Yeow Tee ; Grigoropoulos, Nicholas Francis ; Wong, Esther Kam Yin ; Pang, Jane Wan Lu ; Chia, Burton Kuan Hui ; Kim, Seok Jin ; Yoon, Sang Eun ; Kuo, Ching-Yuan ; Chen, Tsai-Yun ; Huang, Wen-Tsung ; Lee, Ming-Yang ; Ngan, Kai-Cheong ; Liu, Herman ; Yip, Sze-Fai ; Liu, Jie ; Li, Jianyong ; Rabkin, Charles S ; Berndt, Sonja ; Bassig, Bryan ; Hu, Wei ; Li, Yuming ; Zhai, Qiongli ; Shao, Zonghong ; Qiu, Lugui ; Xu, Shuangnian ; Huang, Zhen ; Zhong, Shilong ; Zhang, Yan ; Wang, Xin ; Foo, Jia Nee ; Dai, Juncheng ; Sun, Liangdan ; Wang, Zhenzhen ; Liu, Hong ; Zhou, Hui ; Heng, Chew-Kiat ; Hong, Chew Soo ; Ahn, Jeeyun ; Tin, Aung ; Li, Bo ; Yu, Xueqing
creatorcontribLin, Guo-Wang ; Xu, Caigang ; Chen, Jieping ; Chan, John K C ; Li, Wenyu ; Liu, Weiping ; Shih, Lee-Yung ; Kim, Won Seog ; Tan, Wen ; Peng, Rou-Jun ; Cheah, Daryl Ming Zhe ; Huang, DaChuan ; Cheng, Chee Leong ; Su, Yi-Jiun ; Tan, Soo-Yong ; Wang, Vivien Ya-Fan ; Jia, Wei-Hua ; Li, Ya-Jun ; Gao, Song ; Hu, Zhibin ; Zhang, Furen ; Zeng, Yi-Xin ; Shen, Hongbing ; He, Lin ; Ong, Choon Kiat ; Chanock, Stephen ; Rothman, Nathaniel ; Khor, Chiea Chuen ; Bei, Jin-Xin ; Chiu, Brian ; Li, Zheng ; LAM, Tai Hing ; Xu, Jun ; Ip, Dennis Kai Ming ; Li, Gandi ; Xu, Gang ; Wang, Xiaodong ; Bai, Ou ; Cai, Qing-Qing ; Xia, Yi ; Chen, Jie-Rong ; Luo, Chun-Ling ; Zeng, Yanni ; Wei, Pan-Pan ; Liu, Chu-Jun ; Liu, Yu-Xiang ; Cao, Yu-Lu ; He, Shuai ; Liu, Yang ; Ha, Jeslin Chian Hung ; Khoo, Lay Poh ; Kee, Rebecca Xiangpin ; Liu, Yanhui ; Zhang, Fen ; Chng, Wee Joo ; Chan, Jason Yong Sheng ; Somasundaram, Nagavalli D/O ; Ras, Mohamad Farid Bin Harunal ; Yeoh, Kheng-Wei ; Goh, Yeow Tee ; Grigoropoulos, Nicholas Francis ; Wong, Esther Kam Yin ; Pang, Jane Wan Lu ; Chia, Burton Kuan Hui ; Kim, Seok Jin ; Yoon, Sang Eun ; Kuo, Ching-Yuan ; Chen, Tsai-Yun ; Huang, Wen-Tsung ; Lee, Ming-Yang ; Ngan, Kai-Cheong ; Liu, Herman ; Yip, Sze-Fai ; Liu, Jie ; Li, Jianyong ; Rabkin, Charles S ; Berndt, Sonja ; Bassig, Bryan ; Hu, Wei ; Li, Yuming ; Zhai, Qiongli ; Shao, Zonghong ; Qiu, Lugui ; Xu, Shuangnian ; Huang, Zhen ; Zhong, Shilong ; Zhang, Yan ; Wang, Xin ; Foo, Jia Nee ; Dai, Juncheng ; Sun, Liangdan ; Wang, Zhenzhen ; Liu, Hong ; Zhou, Hui ; Heng, Chew-Kiat ; Hong, Chew Soo ; Ahn, Jeeyun ; Tin, Aung ; Li, Bo ; Yu, Xueqing ; International NKTCL Working Group
descriptionExtranodal 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. 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. 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. 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. 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.
identifier
0ISSN: 1470-2045
1EISSN: 1474-5488
2DOI: 10.1016/S1470-2045(19)30799-5
3PMID: 31879220
languageeng
publisherEngland: Elsevier Ltd
subjectAntigen presentation ; Arrays ; Association analysis ; Binding sites ; Biopsy ; Cancer ; Cell cycle ; Cell proliferation ; Deoxyribonucleic acid ; DNA ; Drb1 protein ; Epstein-Barr virus ; Gene expression ; Gene mapping ; Genes ; Genetic aspects ; Genetic research ; Genetic variance ; Genome-wide association studies ; Genomes ; Genomics ; Histocompatibility antigen HLA ; Immunoregulation ; Infections ; Interleukin 1 ; Interleukin 18 ; Lymphocytes T ; Lymphoma ; Lymphomas ; Malignancy ; Medical research ; Mutation ; Natural killer cells ; Population studies ; Principal components analysis ; Quality control ; Quantitative trait loci ; Risk factors ; Studies ; T cells ; T-cell lymphoma ; Therapeutic applications ; Tumorigenesis
ispartofThe lancet oncology, 2020-02, Vol.21 (2), p.306-316
rights
02020 Elsevier Ltd
1Copyright © 2020 Elsevier Ltd. All rights reserved.
2COPYRIGHT 2020 Elsevier B.V.
32020. Elsevier Ltd
lds50peer_reviewed
citesFETCH-LOGICAL-c372t-3e67ea9a66898e837d2d6126f3d2d1a826bafdf24e40c17e58f6bb033b19b3393
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creatorcontrib
0Lin, Guo-Wang
1Xu, Caigang
2Chen, Jieping
3Chan, John K C
4Li, Wenyu
5Liu, Weiping
6Shih, Lee-Yung
7Kim, Won Seog
8Tan, Wen
9Peng, Rou-Jun
10Cheah, Daryl Ming Zhe
11Huang, DaChuan
12Cheng, Chee Leong
13Su, Yi-Jiun
14Tan, Soo-Yong
15Wang, Vivien Ya-Fan
16Jia, Wei-Hua
17Li, Ya-Jun
18Gao, Song
19Hu, Zhibin
20Zhang, Furen
21Zeng, Yi-Xin
22Shen, Hongbing
23He, Lin
24Ong, Choon Kiat
25Chanock, Stephen
26Rothman, Nathaniel
27Khor, Chiea Chuen
28Bei, Jin-Xin
29Chiu, Brian
30Li, Zheng
31LAM, Tai Hing
32Xu, Jun
33Ip, Dennis Kai Ming
34Li, Gandi
35Xu, Gang
36Wang, Xiaodong
37Bai, Ou
38Cai, Qing-Qing
39Xia, Yi
40Chen, Jie-Rong
41Luo, Chun-Ling
42Zeng, Yanni
43Wei, Pan-Pan
44Liu, Chu-Jun
45Liu, Yu-Xiang
46Cao, Yu-Lu
47He, Shuai
48Liu, Yang
49Ha, Jeslin Chian Hung
50Khoo, Lay Poh
51Kee, Rebecca Xiangpin
52Liu, Yanhui
53Zhang, Fen
54Chng, Wee Joo
55Chan, Jason Yong Sheng
56Somasundaram, Nagavalli D/O
57Ras, Mohamad Farid Bin Harunal
58Yeoh, Kheng-Wei
59Goh, Yeow Tee
60Grigoropoulos, Nicholas Francis
61Wong, Esther Kam Yin
62Pang, Jane Wan Lu
63Chia, Burton Kuan Hui
64Kim, Seok Jin
65Yoon, Sang Eun
66Kuo, Ching-Yuan
67Chen, Tsai-Yun
68Huang, Wen-Tsung
69Lee, Ming-Yang
70Ngan, Kai-Cheong
71Liu, Herman
72Yip, Sze-Fai
73Liu, Jie
74Li, Jianyong
75Rabkin, Charles S
76Berndt, Sonja
77Bassig, Bryan
78Hu, Wei
79Li, Yuming
80Zhai, Qiongli
81Shao, Zonghong
82Qiu, Lugui
83Xu, Shuangnian
84Huang, Zhen
85Zhong, Shilong
86Zhang, Yan
87Wang, Xin
88Foo, Jia Nee
89Dai, Juncheng
90Sun, Liangdan
91Wang, Zhenzhen
92Liu, Hong
93Zhou, Hui
94Heng, Chew-Kiat
95Hong, Chew Soo
96Ahn, Jeeyun
97Tin, Aung
98Li, Bo
99Yu, Xueqing
100International NKTCL Working Group
title
0Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations
1The lancet oncology
addtitleLancet Oncol
descriptionExtranodal 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. 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. 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. 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. 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.
subject
0Antigen presentation
1Arrays
2Association analysis
3Binding sites
4Biopsy
5Cancer
6Cell cycle
7Cell proliferation
8Deoxyribonucleic acid
9DNA
10Drb1 protein
11Epstein-Barr virus
12Gene expression
13Gene mapping
14Genes
15Genetic aspects
16Genetic research
17Genetic variance
18Genome-wide association studies
19Genomes
20Genomics
21Histocompatibility antigen HLA
22Immunoregulation
23Infections
24Interleukin 1
25Interleukin 18
26Lymphocytes T
27Lymphoma
28Lymphomas
29Malignancy
30Medical research
31Mutation
32Natural killer cells
33Population studies
34Principal components analysis
35Quality control
36Quantitative trait loci
37Risk factors
38Studies
39T cells
40T-cell lymphoma
41Therapeutic applications
42Tumorigenesis
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startdate202002
enddate202002
creator
0Lin, Guo-Wang
1Xu, Caigang
2Chen, Jieping
3Chan, John K C
4Li, Wenyu
5Liu, Weiping
6Shih, Lee-Yung
7Kim, Won Seog
8Tan, Wen
9Peng, Rou-Jun
10Cheah, Daryl Ming Zhe
11Huang, DaChuan
12Cheng, Chee Leong
13Su, Yi-Jiun
14Tan, Soo-Yong
15Wang, Vivien Ya-Fan
16Jia, Wei-Hua
17Li, Ya-Jun
18Gao, Song
19Hu, Zhibin
20Zhang, Furen
21Zeng, Yi-Xin
22Shen, Hongbing
23He, Lin
24Ong, Choon Kiat
25Chanock, Stephen
26Rothman, Nathaniel
27Khor, Chiea Chuen
28Bei, Jin-Xin
29Chiu, Brian
30Li, Zheng
31LAM, Tai Hing
32Xu, Jun
33Ip, Dennis Kai Ming
34Li, Gandi
35Xu, Gang
36Wang, Xiaodong
37Bai, Ou
38Cai, Qing-Qing
39Xia, Yi
40Chen, Jie-Rong
41Luo, Chun-Ling
42Zeng, Yanni
43Wei, Pan-Pan
44Liu, Chu-Jun
45Liu, Yu-Xiang
46Cao, Yu-Lu
47He, Shuai
48Liu, Yang
49Ha, Jeslin Chian Hung
50Khoo, Lay Poh
51Kee, Rebecca Xiangpin
52Liu, Yanhui
53Zhang, Fen
54Chng, Wee Joo
55Chan, Jason Yong Sheng
56Somasundaram, Nagavalli D/O
57Ras, Mohamad Farid Bin Harunal
58Yeoh, Kheng-Wei
59Goh, Yeow Tee
60Grigoropoulos, Nicholas Francis
61Wong, Esther Kam Yin
62Pang, Jane Wan Lu
63Chia, Burton Kuan Hui
64Kim, Seok Jin
65Yoon, Sang Eun
66Kuo, Ching-Yuan
67Chen, Tsai-Yun
68Huang, Wen-Tsung
69Lee, Ming-Yang
70Ngan, Kai-Cheong
71Liu, Herman
72Yip, Sze-Fai
73Liu, Jie
74Li, Jianyong
75Rabkin, Charles S
76Berndt, Sonja
77Bassig, Bryan
78Hu, Wei
79Li, Yuming
80Zhai, Qiongli
81Shao, Zonghong
82Qiu, Lugui
83Xu, Shuangnian
84Huang, Zhen
85Zhong, Shilong
86Zhang, Yan
87Wang, Xin
88Foo, Jia Nee
89Dai, Juncheng
90Sun, Liangdan
91Wang, Zhenzhen
92Liu, Hong
93Zhou, Hui
94Heng, Chew-Kiat
95Hong, Chew Soo
96Ahn, Jeeyun
97Tin, Aung
98Li, Bo
99Yu, Xueqing
general
0Elsevier Ltd
1Elsevier B.V
2Elsevier Limited
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creationdate202002
titleGenetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations
authorLin, Guo-Wang ; Xu, Caigang ; Chen, Jieping ; Chan, John K C ; Li, Wenyu ; Liu, Weiping ; Shih, Lee-Yung ; Kim, Won Seog ; Tan, Wen ; Peng, Rou-Jun ; Cheah, Daryl Ming Zhe ; Huang, DaChuan ; Cheng, Chee Leong ; Su, Yi-Jiun ; Tan, Soo-Yong ; Wang, Vivien Ya-Fan ; Jia, Wei-Hua ; Li, Ya-Jun ; Gao, Song ; Hu, Zhibin ; Zhang, Furen ; Zeng, Yi-Xin ; Shen, Hongbing ; He, Lin ; Ong, Choon Kiat ; Chanock, Stephen ; Rothman, Nathaniel ; Khor, Chiea Chuen ; Bei, Jin-Xin ; Chiu, Brian ; Li, Zheng ; LAM, Tai Hing ; Xu, Jun ; Ip, Dennis Kai Ming ; Li, Gandi ; Xu, Gang ; Wang, Xiaodong ; Bai, Ou ; Cai, Qing-Qing ; Xia, Yi ; Chen, Jie-Rong ; Luo, Chun-Ling ; Zeng, Yanni ; Wei, Pan-Pan ; Liu, Chu-Jun ; Liu, Yu-Xiang ; Cao, Yu-Lu ; He, Shuai ; Liu, Yang ; Ha, Jeslin Chian Hung ; Khoo, Lay Poh ; Kee, Rebecca Xiangpin ; Liu, Yanhui ; Zhang, Fen ; Chng, Wee Joo ; Chan, Jason Yong Sheng ; Somasundaram, Nagavalli D/O ; Ras, Mohamad Farid Bin Harunal ; Yeoh, Kheng-Wei ; Goh, Yeow Tee ; Grigoropoulos, Nicholas Francis ; Wong, Esther Kam Yin ; Pang, Jane Wan Lu ; Chia, Burton Kuan Hui ; Kim, Seok Jin ; Yoon, Sang Eun ; Kuo, Ching-Yuan ; Chen, Tsai-Yun ; Huang, Wen-Tsung ; Lee, Ming-Yang ; Ngan, Kai-Cheong ; Liu, Herman ; Yip, Sze-Fai ; Liu, Jie ; Li, Jianyong ; Rabkin, Charles S ; Berndt, Sonja ; Bassig, Bryan ; Hu, Wei ; Li, Yuming ; Zhai, Qiongli ; Shao, Zonghong ; Qiu, Lugui ; Xu, Shuangnian ; Huang, Zhen ; Zhong, Shilong ; Zhang, Yan ; Wang, Xin ; Foo, Jia Nee ; Dai, Juncheng ; Sun, Liangdan ; Wang, Zhenzhen ; Liu, Hong ; Zhou, Hui ; Heng, Chew-Kiat ; Hong, Chew Soo ; Ahn, Jeeyun ; Tin, Aung ; Li, Bo ; Yu, Xueqing
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rsrctypearticles
prefilterarticles
languageeng
creationdate2020
topic
0Antigen presentation
1Arrays
2Association analysis
3Binding sites
4Biopsy
5Cancer
6Cell cycle
7Cell proliferation
8Deoxyribonucleic acid
9DNA
10Drb1 protein
11Epstein-Barr virus
12Gene expression
13Gene mapping
14Genes
15Genetic aspects
16Genetic research
17Genetic variance
18Genome-wide association studies
19Genomes
20Genomics
21Histocompatibility antigen HLA
22Immunoregulation
23Infections
24Interleukin 1
25Interleukin 18
26Lymphocytes T
27Lymphoma
28Lymphomas
29Malignancy
30Medical research
31Mutation
32Natural killer cells
33Population studies
34Principal components analysis
35Quality control
36Quantitative trait loci
37Risk factors
38Studies
39T cells
40T-cell lymphoma
41Therapeutic applications
42Tumorigenesis
toplevel
0peer_reviewed
1online_resources
creatorcontrib
0Lin, Guo-Wang
1Xu, Caigang
2Chen, Jieping
3Chan, John K C
4Li, Wenyu
5Liu, Weiping
6Shih, Lee-Yung
7Kim, Won Seog
8Tan, Wen
9Peng, Rou-Jun
10Cheah, Daryl Ming Zhe
11Huang, DaChuan
12Cheng, Chee Leong
13Su, Yi-Jiun
14Tan, Soo-Yong
15Wang, Vivien Ya-Fan
16Jia, Wei-Hua
17Li, Ya-Jun
18Gao, Song
19Hu, Zhibin
20Zhang, Furen
21Zeng, Yi-Xin
22Shen, Hongbing
23He, Lin
24Ong, Choon Kiat
25Chanock, Stephen
26Rothman, Nathaniel
27Khor, Chiea Chuen
28Bei, Jin-Xin
29Chiu, Brian
30Li, Zheng
31LAM, Tai Hing
32Xu, Jun
33Ip, Dennis Kai Ming
34Li, Gandi
35Xu, Gang
36Wang, Xiaodong
37Bai, Ou
38Cai, Qing-Qing
39Xia, Yi
40Chen, Jie-Rong
41Luo, Chun-Ling
42Zeng, Yanni
43Wei, Pan-Pan
44Liu, Chu-Jun
45Liu, Yu-Xiang
46Cao, Yu-Lu
47He, Shuai
48Liu, Yang
49Ha, Jeslin Chian Hung
50Khoo, Lay Poh
51Kee, Rebecca Xiangpin
52Liu, Yanhui
53Zhang, Fen
54Chng, Wee Joo
55Chan, Jason Yong Sheng
56Somasundaram, Nagavalli D/O
57Ras, Mohamad Farid Bin Harunal
58Yeoh, Kheng-Wei
59Goh, Yeow Tee
60Grigoropoulos, Nicholas Francis
61Wong, Esther Kam Yin
62Pang, Jane Wan Lu
63Chia, Burton Kuan Hui
64Kim, Seok Jin
65Yoon, Sang Eun
66Kuo, Ching-Yuan
67Chen, Tsai-Yun
68Huang, Wen-Tsung
69Lee, Ming-Yang
70Ngan, Kai-Cheong
71Liu, Herman
72Yip, Sze-Fai
73Liu, Jie
74Li, Jianyong
75Rabkin, Charles S
76Berndt, Sonja
77Bassig, Bryan
78Hu, Wei
79Li, Yuming
80Zhai, Qiongli
81Shao, Zonghong
82Qiu, Lugui
83Xu, Shuangnian
84Huang, Zhen
85Zhong, Shilong
86Zhang, Yan
87Wang, Xin
88Foo, Jia Nee
89Dai, Juncheng
90Sun, Liangdan
91Wang, Zhenzhen
92Liu, Hong
93Zhou, Hui
94Heng, Chew-Kiat
95Hong, Chew Soo
96Ahn, Jeeyun
97Tin, Aung
98Li, Bo
99Yu, Xueqing
100International NKTCL Working Group
collection
0PubMed
1CrossRef
2Academic OneFile (A&I only)
3Pharma and Biotech Premium PRO
4ProQuest Central (Corporate)
5Nursing & Allied Health Database
6Oncogenes and Growth Factors Abstracts
7Entrepreneurship Database
8Health & Medical Collection
9ProQuest Central (purchase pre-March 2016)
10Medical Database (Alumni Edition)
11ProQuest Pharma Collection
12Public Health Database
13Lancet Titles
14Hospital Premium Collection
15Hospital Premium Collection (Alumni Edition)
16ProQuest Central (Alumni) (purchase pre-March 2016)
17ProQuest Central (Alumni Edition)
18ProQuest Central
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22AIDS and Cancer Research Abstracts
23ProQuest Business Collection
24ProQuest Health & Medical Complete (Alumni)
25Nursing & Allied Health Database (Alumni Edition)
26Health & Medical Collection (Alumni Edition)
27Medical Database
28Nursing & Allied Health Premium
29ProQuest One Academic Eastern Edition
30ProQuest One Academic
31ProQuest One Academic UKI Edition
32ProQuest Central China
jtitleThe lancet oncology
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Lin, Guo-Wang
1Xu, Caigang
2Chen, Jieping
3Chan, John K C
4Li, Wenyu
5Liu, Weiping
6Shih, Lee-Yung
7Kim, Won Seog
8Tan, Wen
9Peng, Rou-Jun
10Cheah, Daryl Ming Zhe
11Huang, DaChuan
12Cheng, Chee Leong
13Su, Yi-Jiun
14Tan, Soo-Yong
15Wang, Vivien Ya-Fan
16Jia, Wei-Hua
17Li, Ya-Jun
18Gao, Song
19Hu, Zhibin
20Zhang, Furen
21Zeng, Yi-Xin
22Shen, Hongbing
23He, Lin
24Ong, Choon Kiat
25Chanock, Stephen
26Rothman, Nathaniel
27Khor, Chiea Chuen
28Bei, Jin-Xin
29Chiu, Brian
30Li, Zheng
31LAM, Tai Hing
32Xu, Jun
33Ip, Dennis Kai Ming
34Li, Gandi
35Xu, Gang
36Wang, Xiaodong
37Bai, Ou
38Cai, Qing-Qing
39Xia, Yi
40Chen, Jie-Rong
41Luo, Chun-Ling
42Zeng, Yanni
43Wei, Pan-Pan
44Liu, Chu-Jun
45Liu, Yu-Xiang
46Cao, Yu-Lu
47He, Shuai
48Liu, Yang
49Ha, Jeslin Chian Hung
50Khoo, Lay Poh
51Kee, Rebecca Xiangpin
52Liu, Yanhui
53Zhang, Fen
54Chng, Wee Joo
55Chan, Jason Yong Sheng
56Somasundaram, Nagavalli D/O
57Ras, Mohamad Farid Bin Harunal
58Yeoh, Kheng-Wei
59Goh, Yeow Tee
60Grigoropoulos, Nicholas Francis
61Wong, Esther Kam Yin
62Pang, Jane Wan Lu
63Chia, Burton Kuan Hui
64Kim, Seok Jin
65Yoon, Sang Eun
66Kuo, Ching-Yuan
67Chen, Tsai-Yun
68Huang, Wen-Tsung
69Lee, Ming-Yang
70Ngan, Kai-Cheong
71Liu, Herman
72Yip, Sze-Fai
73Liu, Jie
74Li, Jianyong
75Rabkin, Charles S
76Berndt, Sonja
77Bassig, Bryan
78Hu, Wei
79Li, Yuming
80Zhai, Qiongli
81Shao, Zonghong
82Qiu, Lugui
83Xu, Shuangnian
84Huang, Zhen
85Zhong, Shilong
86Zhang, Yan
87Wang, Xin
88Foo, Jia Nee
89Dai, Juncheng
90Sun, Liangdan
91Wang, Zhenzhen
92Liu, Hong
93Zhou, Hui
94Heng, Chew-Kiat
95Hong, Chew Soo
96Ahn, Jeeyun
97Tin, Aung
98Li, Bo
99Yu, Xueqing
aucorpInternational NKTCL Working Group
formatjournal
genrearticle
ristypeJOUR
atitleGenetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study in multiple populations
jtitleThe lancet oncology
addtitleLancet Oncol
date2020-02
risdate2020
volume21
issue2
spage306
epage316
pages306-316
issn1470-2045
eissn1474-5488
abstractExtranodal 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. 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. 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. 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. 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.
copEngland
pubElsevier Ltd
pmid31879220
doi10.1016/S1470-2045(19)30799-5