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Title: Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study
Authors: Li, Zheng
Xia, Yi
Feng, Li-Na
Chen, Jie-Rong
Li, Hong-Min
Cui, Jing
Cai, Qing-Qing
Sim, Kar Seng
Nairismagi, Maarja-Liisa
Laurensia, Yurike
Meah, Wee Yang
Liu, Wen-Sheng
Guo, Yun-Miao
Chen, Li-Zhen
Feng, Qi-Sheng
Pang, Chi Pui
Chen, Li Jia
Chew, Soo Hong 
Ebstein, Richard P
Foo, Jia Nee
Liu, Jianjun
Ha, Jeslin
Khoo, Lay Poh
Chin, Suk Teng
Zeng, Yi-Xin
Aung, Tin
Chowbay, Balram 
Diong, Colin Phipps
Zhang, Fen
Liu, Yan-Hui
Tang, Tiffany
Tao, Miriam
Quek, Richard
Mohamad, Farid
Tan, Soo Yong 
Teh, Bin Tean 
Ng, Siok Bian 
Chng, Wee Joo 
Ong, Choon Kiat 
Okada, Yukinori
Raychaudhuri, Soumya
Lim, Soon Thye
Tan, Wen
Peng, Rou-Jun
Khor, Chiea Chuen
Bei, Jin-Xin
Keywords: Science & Technology
Life Sciences & Biomedicine
Issue Date: 1-Sep-2016
Citation: Li, Zheng, Xia, Yi, Feng, Li-Na, Chen, Jie-Rong, Li, Hong-Min, Cui, Jing, Cai, Qing-Qing, Sim, Kar Seng, Nairismagi, Maarja-Liisa, Laurensia, Yurike, Meah, Wee Yang, Liu, Wen-Sheng, Guo, Yun-Miao, Chen, Li-Zhen, Feng, Qi-Sheng, Pang, Chi Pui, Chen, Li Jia, Chew, Soo Hong, Ebstein, Richard P, Foo, Jia Nee, Liu, Jianjun, Ha, Jeslin, Khoo, Lay Poh, Chin, Suk Teng, Zeng, Yi-Xin, Aung, Tin, Chowbay, Balram, Diong, Colin Phipps, Zhang, Fen, Liu, Yan-Hui, Tang, Tiffany, Tao, Miriam, Quek, Richard, Mohamad, Farid, Tan, Soo Yong, Teh, Bin Tean, Ng, Siok Bian, Chng, Wee Joo, Ong, Choon Kiat, Okada, Yukinori, Raychaudhuri, Soumya, Lim, Soon Thye, Tan, Wen, Peng, Rou-Jun, Khor, Chiea Chuen, Bei, Jin-Xin (2016-09-01). Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study. LANCET ONCOLOGY 17 (9) : 1240-1247. ScholarBank@NUS Repository.
Abstract: Background Extranodal natural killer T-cell lymphoma (NKTCL), nasal type, is a rare and aggressive malignancy that occurs predominantly in Asian and Latin American populations. Although Epstein-Barr virus infection is a known risk factor, other risk factors and the pathogenesis of NKTCL are not well understood. We aimed to identify common genetic variants affecting individual risk of NKTCL. Methods We did a genome-wide association study of 189 patients with extranodal NKTCL, nasal type (WHO classification criteria; cases) and 957 controls from Guangdong province, southern China. We validated our findings in four independent case-control series, including 75 cases from Guangdong province and 296 controls from Hong Kong, 65 cases and 983 controls from Guangdong province, 125 cases and 1110 controls from Beijing (northern China), and 60 cases and 2476 controls from Singapore. We used imputation and conditional logistic regression analyses to fine-map the associations. We also did a meta-analysis of the replication series and of the entire dataset. Findings Associations exceeding the genome-wide significance threshold (p<5 × 10−8) were seen at 51 single-nucleotide polymorphisms (SNPs) mapping to the class II MHC region on chromosome 6, with rs9277378 (located in HLA-DPB1) having the strongest association with NKTCL susceptibility (p=4·21 × 10−19, odds ratio [OR] 1·84 [95% CI 1·61–2·11] in meta-analysis of entire dataset). Imputation-based fine-mapping across the class II MHC region suggests that four aminoacid residues (Gly84-Gly85-Pro86-Met87) in near-complete linkage disequilibrium at the edge of the peptide-binding groove of HLA-DPB1 could account for most of the association between the rs9277378*A risk allele and NKTCL susceptibility (OR 2·38, p value for haplotype 2·32 × 10−14). This association is distinct from MHC associations with Epstein-Barr virus infection. Interpretation To our knowledge, this is the first time that a genetic variant conferring an NKTCL risk is noted at genome-wide significance. This finding underlines the importance of HLA-DP antigen presentation in the pathogenesis of NKTCL. Funding Top-Notch Young Talents Program of China, Special Support Program of Guangdong, Specialized Research Fund for the Doctoral Program of Higher Education (20110171120099), Program for New Century Excellent Talents in University (NCET-11-0529), National Medical Research Council of Singapore (TCR12DEC005), Tanoto Foundation Professorship in Medical Oncology, New Century Foundation Limited, Ling Foundation, Singapore National Cancer Centre Research Fund, and the US National Institutes of Health (1R01AR062886, 5U01GM092691-04, and 1R01AR063759-01A1).
ISSN: 14702045
DOI: 10.1016/S1470-2045(16)30148-6
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