Journal
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE
Volume 104, Issue 3, Pages 240-253Publisher
OXFORD UNIV PRESS INC
DOI: 10.1093/jnci/djr516
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Funding
- L'Institut National du Cancer, France
- Spanish Ministry of Health [FIS 08-1555, 06/02/0073]
- Ministry of Health of the Czech Republic [MZ0 MOU2005]
- German Jose Carreras Leukemia Foundation [DJCLS_R04/08]
- Federal Office for Radiation Protection [StSch4261, StSch4420]
- European Commission [QLK4-CT-2000-00422, FP6-2003-FOOD-2-B]
- La Fondation de France [1999-008471]
- Compagnia di San Paolo - Programma Oncologia
- Health Research Board, Ireland
- Leukaemia Research Fund [08031, 05045]
- Kay Kendall Leukaemia Fund
- United States National Institutes of Health [R01 CA69269]
- Nordic Cancer Union [16-02-D]
- Plan Danmark
- Danish Cancer Research Foundation [41-08]
- Lundbeck Foundation [R19-A2364]
- Danish Cancer Society [DP 08-155]
- Swedish Cancer Society [2009/1084]
- Dutch Cancer Society (KWF) [RUG 2000-2315, RUG 2010-4860]
- Netherlands Organisation of Scientific Research (NWO-MW) [920-03-136]
- Leukaemia & Lymphoma Research [00/73, 06001]
- Cancer Research UK [14136] Funding Source: researchfish
- Medical Research Council [G0401527, G1000143] Funding Source: researchfish
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Accumulating evidence suggests that risk factors for classical Hodgkin lymphoma (cHL) differ by tumor Epstein-Barr virus (EBV) status. This potential etiological heterogeneity is not recognized in current disease classification. We conducted a genome-wide association study of 1200 cHL patients and 6417 control subjects, with validation in an independent replication series, to identify common genetic variants associated with total cHL and subtypes defined by tumor EBV status. Multiple logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) assuming a log-additive genetic model for the variants. All statistical tests were two-sided. Two novel loci associated with total cHL irrespective of EBV status were identified in the major histocompatibility complex region; one resides adjacent to MICB (rs2248462: OR = 0.61, 95% CI = 0.53 to 0.69, P = 1.3 x 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 x 10(-25)) with both results confirmed in an independent replication series. Consistent with previous reports, associations were found between EBV-positive cHL and genetic variants within the class I region (rs2734986, HLA-A: OR = 2.45, 95% CI = 2.00 to 3.00, P = 1.2 x 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 x 10(-10)) and between EBV-negative cHL and rs6903608 within the class II region (rs6903608, HLA-DRA: OR = 2.08, 95% CI = 1.84 to 2.35, P = 6.1 x 10(-31)). The association between rs6903608 and EBV-negative cHL was confined to the nodular sclerosis histological subtype. Evidence for an association between EBV-negative cHL and rs20541 (5q31, IL13: OR = 1.53, 95% CI = 1.32 to 1.76, P = 5.4 x 10(-9)), a variant previously linked to psoriasis and asthma, was observed; however, the evidence for replication was less clear. Notably, one additional psoriasis-associated variant, rs27524 (5q15, ERAP1), showed evidence of an association with cHL in the genome-wide association study (OR = 1.21, 95% CI = 1.10 to 1.33, P = 1.5 x 10(-4)) and replication series (P = .03). Overall, these results provide strong evidence that EBV status is an etiologically important classification of cHL and also suggest that some components of the pathological process are common to both EBV-positive and EBV-negative patients.
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