Genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups

Kevin Y. Urayama; Ruth F. Jarrett; Henrik Hjalgrim; Arjan Diepstra; Yoichiro Kamatani; Amelie Chabrier; Valerie Gaborieau; Anne Boland; Alexandra Nieters; Nikolaus Becker; Lenka Foretova; Yolanda Benavente; Marc Maynadié; Anthony Staines; Lesley Shield; Annette Lake; Dorothy Montgomery; Malcolm Taylor; Karin Ekström Smedby; Rose Marie Amini; Hans Olov Adami; Bengt Glimelius; Bjarke Feenstra; Ilja M. Nolte; Lydia Visser; Gustaaf W. Van Imhoff; Tracy Lightfoot; Pierluigi Cocco; Lambertus Kiemeney; Sita H. Vermeulen; Ivana Holcatova; Lars Vatten; Gary J. MacFarlane; Peter Thomson; David I. Conway; Simone Benhamou; Antonio Agudo; Claire M. Healy; Kim Overvad; Anne Tjønneland; Beatrice Melin; Federico Canzian; Kay Tee Khaw; Ruth C. Travis; Petra H.M. Peeters; Carlos A. González; José Ramón Quirós; María José Sánchez; José María Huerta; Eva Ardanaz; Miren Dorronsoro; Fraçoise Clavel-Chapelon; H. Bas Bueno-De-Mesquita; Elio Riboli; Eve Roman; Paolo Boffetta; Silvia De Sanjosé; Diana Zelenika; Mads Melbye; Anke Van Den Berg; Mark Lathrop; Paul Brennan; James D. McKay

doi:10.1093/jnci/djr516

Genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups

Kevin Y. Urayama, Ruth F. Jarrett, Henrik Hjalgrim, Arjan Diepstra, Yoichiro Kamatani, Amelie Chabrier, Valerie Gaborieau, Anne Boland, Alexandra Nieters, Nikolaus Becker, Lenka Foretova, Yolanda Benavente, Marc Maynadié, Anthony Staines, Lesley Shield, Annette Lake, Dorothy Montgomery, Malcolm Taylor, Karin Ekström Smedby, Rose Marie AminiHans Olov Adami, Bengt Glimelius, Bjarke Feenstra, Ilja M. Nolte, Lydia Visser, Gustaaf W. Van Imhoff, Tracy Lightfoot, Pierluigi Cocco, Lambertus Kiemeney, Sita H. Vermeulen, Ivana Holcatova, Lars Vatten, Gary J. MacFarlane, Peter Thomson, David I. Conway, Simone Benhamou, Antonio Agudo, Claire M. Healy, Kim Overvad, Anne Tjønneland, Beatrice Melin, Federico Canzian, Kay Tee Khaw, Ruth C. Travis, Petra H.M. Peeters, Carlos A. González, José Ramón Quirós, María José Sánchez, José María Huerta, Eva Ardanaz, Miren Dorronsoro, Fraçoise Clavel-Chapelon, H. Bas Bueno-De-Mesquita, Elio Riboli, Eve Roman, Paolo Boffetta, Silvia De Sanjosé, Diana Zelenika, Mads Melbye, Anke Van Den Berg, Mark Lathrop, Paul Brennan, James D. McKay

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Abstract

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.

Original language	English
Pages (from-to)	240-253
Number of pages	14
Journal	Journal of the National Cancer Institute
Volume	104
Issue number	3
DOIs	https://doi.org/10.1093/jnci/djr516
State	Published - 8 Feb 2012

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10.1093/jnci/djr516

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Urayama, K. Y., Jarrett, R. F., Hjalgrim, H., Diepstra, A., Kamatani, Y., Chabrier, A., Gaborieau, V., Boland, A., Nieters, A., Becker, N., Foretova, L., Benavente, Y., Maynadié, M., Staines, A., Shield, L., Lake, A., Montgomery, D., Taylor, M., Smedby, K. E., ... McKay, J. D. (2012). Genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups. Journal of the National Cancer Institute, 104(3), 240-253. https://doi.org/10.1093/jnci/djr516

@article{8c078fda3cfd4780b92d51a31f6cd6de,

title = "Genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups",

abstract = "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.",

author = "Urayama, {Kevin Y.} and Jarrett, {Ruth F.} and Henrik Hjalgrim and Arjan Diepstra and Yoichiro Kamatani and Amelie Chabrier and Valerie Gaborieau and Anne Boland and Alexandra Nieters and Nikolaus Becker and Lenka Foretova and Yolanda Benavente and Marc Maynadi{\'e} and Anthony Staines and Lesley Shield and Annette Lake and Dorothy Montgomery and Malcolm Taylor and Smedby, {Karin Ekstr{\"o}m} and Amini, {Rose Marie} and Adami, {Hans Olov} and Bengt Glimelius and Bjarke Feenstra and Nolte, {Ilja M.} and Lydia Visser and {Van Imhoff}, {Gustaaf W.} and Tracy Lightfoot and Pierluigi Cocco and Lambertus Kiemeney and Vermeulen, {Sita H.} and Ivana Holcatova and Lars Vatten and MacFarlane, {Gary J.} and Peter Thomson and Conway, {David I.} and Simone Benhamou and Antonio Agudo and Healy, {Claire M.} and Kim Overvad and Anne Tj{\o}nneland and Beatrice Melin and Federico Canzian and Khaw, {Kay Tee} and Travis, {Ruth C.} and Peeters, {Petra H.M.} and Gonz{\'a}lez, {Carlos A.} and Quir{\'o}s, {Jos{\'e} Ram{\'o}n} and S{\'a}nchez, {Mar{\'i}a Jos{\'e}} and Huerta, {Jos{\'e} Mar{\'i}a} and Eva Ardanaz and Miren Dorronsoro and Fra{\c c}oise Clavel-Chapelon and Bueno-De-Mesquita, {H. Bas} and Elio Riboli and Eve Roman and Paolo Boffetta and {De Sanjos{\'e}}, Silvia and Diana Zelenika and Mads Melbye and {Van Den Berg}, Anke and Mark Lathrop and Paul Brennan and McKay, {James D.}",

note = "Funding Information: This work was supported by L{\textquoteright}Institut National du Cancer, France; Spanish Ministry of Health grant CIBERESP (FIS 08-1555 and 06/02/0073 to S.D.S.); Ministry of Health of the Czech Republic (MZ0 MOU2005 to L.F.); German Jos{\'e} Carreras Leukemia Foundation (DJCLS_R04/08 to A.N.); Federal Office for Radiation Protection (StSch4261 and StSch4420 to N.B.); European Commission 5th Framework Program Quality of Life (QLK4-CT-2000-00422 to P.Br.); European Commission 6th Framework Program (FP6-2003-FOOD-2-B to P.Bo.); La Fondation de France (1999-008471 to M.Ma.); Compagnia di San Paolo - Programma Oncologia (P.C.); Health Research Board, Ireland (A.S.); Leukaemia Research Fund (08031 and 05045 to R.F.J.); Kay Kendall Leukaemia Fund (R.F.J. and M.T.); United States National Institutes of Health (R01 CA69269 to M.Me.), Nordic Cancer Union (16-02-D to H.H.); Plan Danmark; Danish Cancer Research Foundation (41-08 to M.Me.); Lundbeck Foundation (R19-A2364 to H.H.); Danish Cancer Society (DP 08-155 to H.H.); Swedish Cancer Society (2009/1084 to K.E.S.); Dutch Cancer Society (KWF grants RUG 2000-2315 and RUG 2010-4860 to A.v.d.B.); the Netherlands Organisation of Scientific Research (NWO-MW grant 920-03-136 to A.D.); Leukaemia & Lymphoma Research (00/73 and 06001 to E.Ro.).",

year = "2012",

month = feb,

day = "8",

doi = "10.1093/jnci/djr516",

language = "English",

volume = "104",

pages = "240--253",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "3",

}

Urayama, KY, Jarrett, RF, Hjalgrim, H, Diepstra, A, Kamatani, Y, Chabrier, A, Gaborieau, V, Boland, A, Nieters, A, Becker, N, Foretova, L, Benavente, Y, Maynadié, M, Staines, A, Shield, L, Lake, A, Montgomery, D, Taylor, M, Smedby, KE, Amini, RM, Adami, HO, Glimelius, B, Feenstra, B, Nolte, IM, Visser, L, Van Imhoff, GW, Lightfoot, T, Cocco, P, Kiemeney, L, Vermeulen, SH, Holcatova, I, Vatten, L, MacFarlane, GJ, Thomson, P, Conway, DI, Benhamou, S, Agudo, A, Healy, CM, Overvad, K, Tjønneland, A, Melin, B, Canzian, F, Khaw, KT, Travis, RC, Peeters, PHM, González, CA, Quirós, JR, Sánchez, MJ, Huerta, JM, Ardanaz, E, Dorronsoro, M, Clavel-Chapelon, F, Bueno-De-Mesquita, HB, Riboli, E, Roman, E, Boffetta, P, De Sanjosé, S, Zelenika, D, Melbye, M, Van Den Berg, A, Lathrop, M, Brennan, P & McKay, JD 2012, 'Genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups', Journal of the National Cancer Institute, vol. 104, no. 3, pp. 240-253. https://doi.org/10.1093/jnci/djr516

TY - JOUR

T1 - Genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups

AU - Urayama, Kevin Y.

AU - Jarrett, Ruth F.

AU - Hjalgrim, Henrik

AU - Diepstra, Arjan

AU - Kamatani, Yoichiro

AU - Chabrier, Amelie

AU - Gaborieau, Valerie

AU - Boland, Anne

AU - Nieters, Alexandra

AU - Becker, Nikolaus

AU - Foretova, Lenka

AU - Benavente, Yolanda

AU - Maynadié, Marc

AU - Staines, Anthony

AU - Shield, Lesley

AU - Lake, Annette

AU - Montgomery, Dorothy

AU - Taylor, Malcolm

AU - Smedby, Karin Ekström

AU - Amini, Rose Marie

AU - Adami, Hans Olov

AU - Glimelius, Bengt

AU - Feenstra, Bjarke

AU - Nolte, Ilja M.

AU - Visser, Lydia

AU - Van Imhoff, Gustaaf W.

AU - Lightfoot, Tracy

AU - Cocco, Pierluigi

AU - Kiemeney, Lambertus

AU - Vermeulen, Sita H.

AU - Holcatova, Ivana

AU - Vatten, Lars

AU - MacFarlane, Gary J.

AU - Thomson, Peter

AU - Conway, David I.

AU - Benhamou, Simone

AU - Agudo, Antonio

AU - Healy, Claire M.

AU - Overvad, Kim

AU - Tjønneland, Anne

AU - Melin, Beatrice

AU - Canzian, Federico

AU - Khaw, Kay Tee

AU - Travis, Ruth C.

AU - Peeters, Petra H.M.

AU - González, Carlos A.

AU - Quirós, José Ramón

AU - Sánchez, María José

AU - Huerta, José María

AU - Ardanaz, Eva

AU - Dorronsoro, Miren

AU - Clavel-Chapelon, Fraçoise

AU - Bueno-De-Mesquita, H. Bas

AU - Riboli, Elio

AU - Roman, Eve

AU - Boffetta, Paolo

AU - De Sanjosé, Silvia

AU - Zelenika, Diana

AU - Melbye, Mads

AU - Van Den Berg, Anke

AU - Lathrop, Mark

AU - Brennan, Paul

AU - McKay, James D.

N1 - Funding Information: This work was supported by L’Institut National du Cancer, France; Spanish Ministry of Health grant CIBERESP (FIS 08-1555 and 06/02/0073 to S.D.S.); Ministry of Health of the Czech Republic (MZ0 MOU2005 to L.F.); German José Carreras Leukemia Foundation (DJCLS_R04/08 to A.N.); Federal Office for Radiation Protection (StSch4261 and StSch4420 to N.B.); European Commission 5th Framework Program Quality of Life (QLK4-CT-2000-00422 to P.Br.); European Commission 6th Framework Program (FP6-2003-FOOD-2-B to P.Bo.); La Fondation de France (1999-008471 to M.Ma.); Compagnia di San Paolo - Programma Oncologia (P.C.); Health Research Board, Ireland (A.S.); Leukaemia Research Fund (08031 and 05045 to R.F.J.); Kay Kendall Leukaemia Fund (R.F.J. and M.T.); United States National Institutes of Health (R01 CA69269 to M.Me.), Nordic Cancer Union (16-02-D to H.H.); Plan Danmark; Danish Cancer Research Foundation (41-08 to M.Me.); Lundbeck Foundation (R19-A2364 to H.H.); Danish Cancer Society (DP 08-155 to H.H.); Swedish Cancer Society (2009/1084 to K.E.S.); Dutch Cancer Society (KWF grants RUG 2000-2315 and RUG 2010-4860 to A.v.d.B.); the Netherlands Organisation of Scientific Research (NWO-MW grant 920-03-136 to A.D.); Leukaemia & Lymphoma Research (00/73 and 06001 to E.Ro.).

PY - 2012/2/8

Y1 - 2012/2/8

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84856845730&partnerID=8YFLogxK

U2 - 10.1093/jnci/djr516

DO - 10.1093/jnci/djr516

M3 - Article

C2 - 22286212

AN - SCOPUS:84856845730

SN - 0027-8874

VL - 104

SP - 240

EP - 253

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 3

ER -

Genome-wide association study of classical hodgkin lymphoma and epstein-barr virus status-defined subgroups

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