• Zheng Li, Yi Xia, Li-Na Feng, Jie-Rong Chen, Hong-Min Li, Jing Cui, Qing-Qing Cai, Kar Seng Sim, Maarja-Liisa Nairismägi, Yurike Laurensia, Wee Yang Meah, Wen-Sheng Liu, Yun-Miao Guo, Li-Zhen Chen, Qi-Sheng Feng, Chi Pui Pang, Li Jia Chen, Soo Hong Chew, Richard P Ebstein, Jia Nee Foo, Jianjun Liu, Jeslin Ha, Lay Poh Khoo, Suk Teng Chin, Yi-Xin Zeng, Tin Aung, Balram Chowbay, Colin Phipps Diong, Fen Zhang, Yan-Hui Liu, Tiffany Tang, Miriam Tao, Richard Quek, Farid Mohamad, Soo Yong Tan, Bin Tean Teh, Siok Bian Ng, Wee Joo Chng, Choon Kiat Ong, Yukinori Okada, Soumya Raychaudhuri, Soon Thye Lim, Wen Tan, Rou-Jun Peng, Chiea Chuen Khor, and Jin-Xin Bei.
• 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.
• Lancet Oncol. 2016 Sep 1; 17 (9): 1240-7.

BackgroundExtranodal 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.MethodsWe 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.FindingsAssociations 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.InterpretationTo 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.FundingTop-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).Copyright © 2016 Elsevier Ltd. All rights reserved.

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