BACKGROUND: 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. METHODS: 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. RESULTS: 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 × 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 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 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 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 × 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 × 10(-4)) and replication series (P = .03). CONCLUSION: 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.
BACKGROUND: 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. METHODS: 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. RESULTS: 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 × 10(-13)) and the other at HLA-DRA (rs2395185: OR = 0.56, 95% CI = 0.50 to 0.62, P = 8.3 × 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 × 10(-15); rs6904029, HCG9: OR = 0.46, 95% CI = 0.36 to 0.59, P = 5.5 × 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 × 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 × 10(-4)) and replication series (P = .03). CONCLUSION: 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.
Authors: P E Graves; M Kabesch; M Halonen; C J Holberg; M Baldini; C Fritzsch; S K Weiland; R P Erickson; E von Mutius; F D Martinez Journal: J Allergy Clin Immunol Date: 2000-03 Impact factor: 10.793
Authors: Alkes L Price; Nick J Patterson; Robert M Plenge; Michael E Weinblatt; Nancy A Shadick; David Reich Journal: Nat Genet Date: 2006-07-23 Impact factor: 38.330
Authors: Freda E Alexander; Davia J Lawrence; June Freeland; Andrew S Krajewski; Brian Angus; G Malcolm Taylor; Ruth F Jarrett Journal: Int J Cancer Date: 2003-11-01 Impact factor: 7.396
Authors: Frank D Vladich; Susan M Brazille; Debra Stern; Michael L Peck; Raffaella Ghittoni; Donata Vercelli Journal: J Clin Invest Date: 2005-03 Impact factor: 14.808
Authors: Ola Landgren; Eric A Engels; Ruth M Pfeiffer; Gloria Gridley; Lene Mellemkjaer; Jørgen H Olsen; Kimberly F Kerstann; William Wheeler; Kari Hemminki; Martha S Linet; Lynn R Goldin Journal: J Natl Cancer Inst Date: 2006-09-20 Impact factor: 13.506
Authors: A Diepstra; M Niens; E Vellenga; G W van Imhoff; I M Nolte; M Schaapveld; G van der Steege; A van den Berg; R E Kibbelaar; G J te Meerman; S Poppema Journal: Lancet Date: 2005 Jun 25-Jul 1 Impact factor: 79.321
Authors: Margaret L Gulley; Sally L Glaser; Fiona E Craig; Michael Borowitz; Risa B Mann; Sarah J Shema; Richard F Ambinder Journal: Am J Clin Pathol Date: 2002-02 Impact factor: 2.493
Authors: Rajan P Nair; Kristina Callis Duffin; Cynthia Helms; Jun Ding; Philip E Stuart; David Goldgar; Johann E Gudjonsson; Yun Li; Trilokraj Tejasvi; Bing-Jian Feng; Andreas Ruether; Stefan Schreiber; Michael Weichenthal; Dafna Gladman; Proton Rahman; Steven J Schrodi; Sampath Prahalad; Stephen L Guthery; Judith Fischer; Wilson Liao; Pui-Yan Kwok; Alan Menter; G Mark Lathrop; Carol A Wise; Ann B Begovich; John J Voorhees; James T Elder; Gerald G Krueger; Anne M Bowcock; Gonçalo R Abecasis Journal: Nat Genet Date: 2009-01-25 Impact factor: 38.330
Authors: Hervé Ghesquières; Matthew J Maurer; Olivier Casasnovas; Stephen M Ansell; Beth R Larrabee; Eva Lech-Maranda; Anne J Novak; Anne-Laure Borrel; Susan L Slager; Pauline Brice; Cristine Allmer; Annie Brion; Steven C Ziesmer; Franck Morschhauser; Thomas M Habermann; Isabelle Gaillard; Brian K Link; Aspasia Stamatoullas; Christophe Fermé; Ahmet Dogan; William R Macon; Josée Audouin; James R Cerhan; Gilles Salles Journal: Cytokine Date: 2013-09-03 Impact factor: 3.861
Authors: Amy M Linabery; Erik B Erhardt; Michaela R Richardson; Richard F Ambinder; Debra L Friedman; Sally L Glaser; Alain Monnereau; Logan G Spector; Julie A Ross; Seymour Grufferman Journal: Int J Cancer Date: 2015-05-19 Impact factor: 7.396
Authors: Janine Altmüller; Britta Haenisch; Amit Kawalia; Markus Menzen; Markus M Nöthen; Heide Fier; Gerhard J Molderings Journal: Immunogenetics Date: 2017-04-06 Impact factor: 2.846
Authors: Hauke Thomsen; Miguel Inacio da Silva Filho; Asta Försti; Michael Fuchs; Sabine Ponader; Elke Pogge von Strandmann; Lewin Eisele; Stefan Herms; Per Hofmann; Jan Sundquist; Andreas Engert; Kari Hemminki Journal: Eur J Hum Genet Date: 2014-09-17 Impact factor: 4.246
Authors: Lynn I Levin; Elizabeth C Breen; Brenda M Birmann; Julie L Batista; Larry I Magpantay; Yuanzhang Li; Richard F Ambinder; Nancy E Mueller; Otoniel Martínez-Maza Journal: Cancer Epidemiol Biomarkers Prev Date: 2017-03-24 Impact factor: 4.254
Authors: Amy M Linabery; Erik B Erhardt; Rachel K Fonstad; Richard F Ambinder; Greta R Bunin; Julie A Ross; Logan G Spector; Seymour Grufferman Journal: Int J Cancer Date: 2014-03-18 Impact factor: 7.396