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

Li Z 1 , Xia Y 2 , Feng LN 2 , Chen JR 2 , Li HM 3 , Cui J 4 Show all authors , Cai QQ 2 , Sim KS 5 , Nairismägi ML 6 , Laurensia Y 6 , Meah WY 5 , Liu WS 2 , Guo YM 2 , Chen LZ 2 , Feng QS 2 , Pang CP 7 , Chen LJ 7 , Chew SH 8 , Ebstein RP 9 , Foo JN 5 , Liu J 5 , Ha J 6 , Khoo LP 6 , Chin ST 6 , Zeng YX 10 , Aung T 11 , Chowbay B 12 , Diong CP 13 , Zhang F 14 , Liu YH 14 , Tang T 15 , Tao M 15 , Quek R 15 , Mohamad F 15 , Tan SY 16 , Teh BT 17 , Ng SB 18 , Chng WJ 19 , Ong CK 6 , Okada Y 20 , Raychaudhuri S 21 , Lim ST 22 , Tan W 3 , Peng RJ 2 , Khor CC 23 , Bei JX 24

Affiliations 

  • 1 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
  • 2 Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
  • 3 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
  • 4 Division of Rheumatology, Immunology, and Allergy, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
  • 5 Genome Institute of Singapore, Singapore
  • 6 Lymphoma Genomic Translational Research Laboratory, National Cancer Centre Singapore, Singapore
  • 7 Department of Ophthalmology and Visual Sciences, The Chinese University of Hong Kong, Hong Kong Special Administrative Region, China
  • 8 Department of Economics, National University of Singapore, Singapore
  • 9 Department of Psychology, National University of Singapore, Singapore
  • 10 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
  • 11 Singapore Eye Research Institute, Singapore
  • 12 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
  • 13 Department of Haematology, Singapore General Hospital, Singapore
  • 14 Department of Pathology, Guangdong General Hospital, Guangzhou, China
  • 15 Division of Medical Oncology, National Cancer Centre Singapore, Singapore
  • 16 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
  • 17 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
  • 18 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
  • 19 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
  • 20 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
  • 21 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
  • 22 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
  • 23 Genome Institute of Singapore, Singapore; Singapore Eye Research Institute, Singapore; Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
  • 24 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
Lancet Oncol, 2016 Sep;17(9):1240-7.
PMID: 27470079 DOI: 10.1016/S1470-2045(16)30148-6

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).

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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