title: Genetic risk of extranodal natural killer T-cell lymphoma: a genome-wide association study.
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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
  
  
  BACKGROUND
  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).
authors.affiliation: 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.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Li-Na
authors.initials: LN
authors.lastname: Feng
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Jie-Rong
authors.initials: JR
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Molecular Oncology, Beijing, China; Department of Etiology and Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, Beijing, China; Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Hong-Min
authors.initials: HM
authors.lastname: Li
authors.affiliation: Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Cui
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Qing-Qing
authors.initials: QQ
authors.lastname: Cai
authors.affiliation: Genome Institute of Singapore, Singapore.
authors.forename: Kar Seng
authors.initials: KS
authors.lastname: Sim
authors.affiliation: Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Singapore.
authors.forename: Maarja-Liisa
authors.initials: ML
authors.lastname: Nairismägi
authors.affiliation: Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Singapore.
authors.forename: Yurike
authors.initials: Y
authors.lastname: Laurensia
authors.affiliation: Genome Institute of Singapore, Singapore.
authors.forename: Wee Yang
authors.initials: WY
authors.lastname: Meah
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Wen-Sheng
authors.initials: WS
authors.lastname: Liu
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Yun-Miao
authors.initials: YM
authors.lastname: Guo
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Li-Zhen
authors.initials: LZ
authors.lastname: Chen
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Qi-Sheng
authors.initials: QS
authors.lastname: Feng
authors.affiliation: Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Chi Pui
authors.initials: CP
authors.lastname: Pang
authors.affiliation: Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China.
authors.forename: Li Jia
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: Department of Economics, National University of Singapore, Singapore.
authors.forename: Soo Hong
authors.initials: SH
authors.lastname: Chew
authors.affiliation: Department of Psychology, National University of Singapore, Singapore.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Ebstein
authors.affiliation: Genome Institute of Singapore, Singapore.
authors.forename: Jia Nee
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authors.affiliation: Genome Institute of Singapore, Singapore.
authors.forename: Jianjun
authors.initials: J
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authors.affiliation: Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Singapore.
authors.forename: Jeslin
authors.initials: J
authors.lastname: Ha
authors.affiliation: Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Singapore.
authors.forename: Lay Poh
authors.initials: LP
authors.lastname: Khoo
authors.affiliation: Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Singapore.
authors.forename: Suk Teng
authors.initials: ST
authors.lastname: Chin
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; Beijing Hospital, Beijing, China.
authors.forename: Yi-Xin
authors.initials: YX
authors.lastname: Zeng
authors.affiliation: Singapore Eye Research Institute, Singapore.
authors.forename: Tin
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authors.affiliation: Laboratory of Clinical Pharmacology, Division of Medical Sciences, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore; Clinical Pharmacology, SingHealth, Singapore; Office of Clinical Sciences, Duke-National University of Singapore Medical School, Singapore.
authors.forename: Balram
authors.initials: B
authors.lastname: Chowbay
authors.affiliation: Department of Haematology, Singapore General Hospital, Singapore.
authors.forename: Colin Phipps
authors.initials: CP
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authors.affiliation: Department of Pathology, Guangdong General Hospital, Guangzhou, China.
authors.forename: Fen
authors.initials: F
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authors.affiliation: Department of Pathology, Guangdong General Hospital, Guangzhou, China.
authors.forename: Yan-Hui
authors.initials: YH
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authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
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authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Miriam
authors.initials: M
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authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
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authors.initials: R
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authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore.
authors.forename: Farid
authors.initials: F
authors.lastname: Mohamad
authors.affiliation: Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Department of Pathology, Singapore General Hospital, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore; Department of Pathology, University of Malaya, Kuala Lumpur, Malaysia; Department of Pathology, National University of Singapore, Singapore.
authors.forename: Soo Yong
authors.initials: SY
authors.lastname: Tan
authors.affiliation: Program in Cancer and Stem Cell Biology, Duke-National University of Singapore Medical School, Singapore; Institute of Molecular and Cell Biology, A*STAR, Singapore; Laboratory of Cancer Epigenome, Division of Medical Sciences, National Cancer Centre Singapore, Singapore; Cancer Science Institute of Singapore, National University of Singapore, Singapore.
authors.forename: Bin Tean
authors.initials: BT
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authors.affiliation: Department of Pathology, 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.
authors.forename: Siok Bian
authors.initials: SB
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authors.affiliation: Cancer Science Institute of Singapore, National University of Singapore, Singapore; Department of Haematology-Oncology, National University Cancer Institute of Singapore, National University Health System, Singapore.
authors.forename: Wee Joo
authors.initials: WJ
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authors.affiliation: Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Singapore.
authors.forename: Choon Kiat
authors.initials: CK
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authors.affiliation: Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan; Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan; Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Okada
authors.affiliation: Division of Genetics, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Division of Rheumatology, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Partners Center for Personalized Genetic Medicine, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Institute of Inflammation and Repair, University of Manchester, Manchester, UK; Rheumatology Unit, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Soumya
authors.initials: S
authors.lastname: Raychaudhuri
authors.affiliation: Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Singapore; Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Office of Education, Duke-National University of Singapore Medical School, Singapore.
authors.forename: Soon Thye
authors.initials: ST
authors.lastname: Lim
authors.affiliation: State Key Laboratory of Molecular Oncology, Beijing, China; Department of Etiology and Carcinogenesis, Beijing Key Laboratory for Carcinogenesis and Cancer Prevention, Beijing, China; Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Tan
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
authors.forename: Rou-Jun
authors.initials: RJ
authors.lastname: Peng
authors.affiliation: Genome Institute of Singapore, Singapore; Singapore Eye Research Institute, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
authors.forename: Chiea Chuen
authors.initials: CC
authors.lastname: Khor
authors.affiliation: 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; Center for Precision Medicine, Sun Yat-Sen University, Guangzhou, China. Electronic address: beijx@sysucc.org.cn.
authors.forename: Jin-Xin
authors.initials: JX
authors.lastname: Bei
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D002681:China; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D054391:Lymphoma, Extranodal NK-T-Cell / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011379:Prognosis; D012307:Risk Factors; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor