Genome-Wide association study of event-free survival in diffuse large B-cell lymphoma treated with immunochemotherapy

Hervé Ghesquieres, Susan L Slager, Fabrice Jardin, Amelie S. Veron, Yan Asmann, Matthew J. Maurer, Thierry Fest, Thomas Matthew Habermann, Marie C. Bene, Anne J Novak, Sylvain Mareschal, Corinne Haioun, Thierry Lamy, Stephen Maxted Ansell, Herve Tilly, Thomas Elmer Witzig, George J. Weiner, Andrew L Feldman, Ahmet Dogan, Julie M CunninghamCurtis L. Olswold, Thierry Jo Molina, Brian K. Link, Noel Milpied, David G. Cox, Gilles A. Salles, James R Cerhan

Research output: Contribution to journalArticle

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Abstract

Purpose We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Methods We conducted a meta-analysis of two genome-wide association study data sets, one from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and the other from the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa-Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single nucleotide polymorphisms were then genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang (GOELAMS) -075 randomized trial (N = 294). We calculated the hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) using a log-additive genetic model with adjustment for age, sex, and age-adjusted International Prognostic Index. Results In a meta-analysis of the four studies, the top loci for EFS were marked by rs7712513 at 5q23.2 (near SNX2 and SNCAIP; HR, 1.39; 95% CI, 1.23 to 1.57; P = 2.08 × 10-7), and rs7765004 at 6q21 (near MARCKS and HDAC2; HR, 1.38; 95% CI, 1.22 to 1.57; P = 7.09 × 10-7), although they did not reach conventional genome-wide significance (P = 5 × 10-8). Both rs7712513 (HR, 1.49; 95% CI, 1.29 to 1.72; P = 3.53 × 10-8) and rs7765004 (HR, 1.47; 95% CI, 1.27 to 1.71; P = 5.36 × 10-7) were also associated with OS. In exploratory analyses, a two-single nucleotide polymorphism risk score was highly predictive of EFS (P = 1.78 × 10-12) and was independent of treatment, IPI, and cell-of-origin classification. Conclusion Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with EFS and OS in patients with diffuse large B-cell lymphoma treated with immunochemotherapy, suggesting novel biology and the potential contribution of host genetics to the prognosis of this aggressive malignancy.

Original languageEnglish (US)
Pages (from-to)3930-3937
Number of pages8
JournalJournal of Clinical Oncology
Volume33
Issue number33
DOIs
StatePublished - Nov 20 2015

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Lymphoma, Large B-Cell, Diffuse
Genome-Wide Association Study
Disease-Free Survival
Single Nucleotide Polymorphism
Survival
Meta-Analysis
Lymphoma
Molecular Epidemiology
Genetic Models
Research
Observational Studies
Clinical Trials
Genome
Prospective Studies
Neoplasms
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Genome-Wide association study of event-free survival in diffuse large B-cell lymphoma treated with immunochemotherapy. / Ghesquieres, Hervé; Slager, Susan L; Jardin, Fabrice; Veron, Amelie S.; Asmann, Yan; Maurer, Matthew J.; Fest, Thierry; Habermann, Thomas Matthew; Bene, Marie C.; Novak, Anne J; Mareschal, Sylvain; Haioun, Corinne; Lamy, Thierry; Ansell, Stephen Maxted; Tilly, Herve; Witzig, Thomas Elmer; Weiner, George J.; Feldman, Andrew L; Dogan, Ahmet; Cunningham, Julie M; Olswold, Curtis L.; Molina, Thierry Jo; Link, Brian K.; Milpied, Noel; Cox, David G.; Salles, Gilles A.; Cerhan, James R.

In: Journal of Clinical Oncology, Vol. 33, No. 33, 20.11.2015, p. 3930-3937.

Research output: Contribution to journalArticle

Ghesquieres, H, Slager, SL, Jardin, F, Veron, AS, Asmann, Y, Maurer, MJ, Fest, T, Habermann, TM, Bene, MC, Novak, AJ, Mareschal, S, Haioun, C, Lamy, T, Ansell, SM, Tilly, H, Witzig, TE, Weiner, GJ, Feldman, AL, Dogan, A, Cunningham, JM, Olswold, CL, Molina, TJ, Link, BK, Milpied, N, Cox, DG, Salles, GA & Cerhan, JR 2015, 'Genome-Wide association study of event-free survival in diffuse large B-cell lymphoma treated with immunochemotherapy', Journal of Clinical Oncology, vol. 33, no. 33, pp. 3930-3937. https://doi.org/10.1200/JCO.2014.60.2573
Ghesquieres, Hervé ; Slager, Susan L ; Jardin, Fabrice ; Veron, Amelie S. ; Asmann, Yan ; Maurer, Matthew J. ; Fest, Thierry ; Habermann, Thomas Matthew ; Bene, Marie C. ; Novak, Anne J ; Mareschal, Sylvain ; Haioun, Corinne ; Lamy, Thierry ; Ansell, Stephen Maxted ; Tilly, Herve ; Witzig, Thomas Elmer ; Weiner, George J. ; Feldman, Andrew L ; Dogan, Ahmet ; Cunningham, Julie M ; Olswold, Curtis L. ; Molina, Thierry Jo ; Link, Brian K. ; Milpied, Noel ; Cox, David G. ; Salles, Gilles A. ; Cerhan, James R. / Genome-Wide association study of event-free survival in diffuse large B-cell lymphoma treated with immunochemotherapy. In: Journal of Clinical Oncology. 2015 ; Vol. 33, No. 33. pp. 3930-3937.
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title = "Genome-Wide association study of event-free survival in diffuse large B-cell lymphoma treated with immunochemotherapy",
abstract = "Purpose We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Methods We conducted a meta-analysis of two genome-wide association study data sets, one from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and the other from the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa-Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single nucleotide polymorphisms were then genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and the Groupe Ouest-Est des Leuc{\'e}mies Aigu{\"e}s et Maladies du Sang (GOELAMS) -075 randomized trial (N = 294). We calculated the hazard ratios (HRs) and 95{\%} CIs for event-free survival (EFS) and overall survival (OS) using a log-additive genetic model with adjustment for age, sex, and age-adjusted International Prognostic Index. Results In a meta-analysis of the four studies, the top loci for EFS were marked by rs7712513 at 5q23.2 (near SNX2 and SNCAIP; HR, 1.39; 95{\%} CI, 1.23 to 1.57; P = 2.08 × 10-7), and rs7765004 at 6q21 (near MARCKS and HDAC2; HR, 1.38; 95{\%} CI, 1.22 to 1.57; P = 7.09 × 10-7), although they did not reach conventional genome-wide significance (P = 5 × 10-8). Both rs7712513 (HR, 1.49; 95{\%} CI, 1.29 to 1.72; P = 3.53 × 10-8) and rs7765004 (HR, 1.47; 95{\%} CI, 1.27 to 1.71; P = 5.36 × 10-7) were also associated with OS. In exploratory analyses, a two-single nucleotide polymorphism risk score was highly predictive of EFS (P = 1.78 × 10-12) and was independent of treatment, IPI, and cell-of-origin classification. Conclusion Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with EFS and OS in patients with diffuse large B-cell lymphoma treated with immunochemotherapy, suggesting novel biology and the potential contribution of host genetics to the prognosis of this aggressive malignancy.",
author = "Herv{\'e} Ghesquieres and Slager, {Susan L} and Fabrice Jardin and Veron, {Amelie S.} and Yan Asmann and Maurer, {Matthew J.} and Thierry Fest and Habermann, {Thomas Matthew} and Bene, {Marie C.} and Novak, {Anne J} and Sylvain Mareschal and Corinne Haioun and Thierry Lamy and Ansell, {Stephen Maxted} and Herve Tilly and Witzig, {Thomas Elmer} and Weiner, {George J.} and Feldman, {Andrew L} and Ahmet Dogan and Cunningham, {Julie M} and Olswold, {Curtis L.} and Molina, {Thierry Jo} and Link, {Brian K.} and Noel Milpied and Cox, {David G.} and Salles, {Gilles A.} and Cerhan, {James R}",
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month = "11",
day = "20",
doi = "10.1200/JCO.2014.60.2573",
language = "English (US)",
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pages = "3930--3937",
journal = "Journal of Clinical Oncology",
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TY - JOUR

T1 - Genome-Wide association study of event-free survival in diffuse large B-cell lymphoma treated with immunochemotherapy

AU - Ghesquieres, Hervé

AU - Slager, Susan L

AU - Jardin, Fabrice

AU - Veron, Amelie S.

AU - Asmann, Yan

AU - Maurer, Matthew J.

AU - Fest, Thierry

AU - Habermann, Thomas Matthew

AU - Bene, Marie C.

AU - Novak, Anne J

AU - Mareschal, Sylvain

AU - Haioun, Corinne

AU - Lamy, Thierry

AU - Ansell, Stephen Maxted

AU - Tilly, Herve

AU - Witzig, Thomas Elmer

AU - Weiner, George J.

AU - Feldman, Andrew L

AU - Dogan, Ahmet

AU - Cunningham, Julie M

AU - Olswold, Curtis L.

AU - Molina, Thierry Jo

AU - Link, Brian K.

AU - Milpied, Noel

AU - Cox, David G.

AU - Salles, Gilles A.

AU - Cerhan, James R

PY - 2015/11/20

Y1 - 2015/11/20

N2 - Purpose We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Methods We conducted a meta-analysis of two genome-wide association study data sets, one from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and the other from the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa-Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single nucleotide polymorphisms were then genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang (GOELAMS) -075 randomized trial (N = 294). We calculated the hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) using a log-additive genetic model with adjustment for age, sex, and age-adjusted International Prognostic Index. Results In a meta-analysis of the four studies, the top loci for EFS were marked by rs7712513 at 5q23.2 (near SNX2 and SNCAIP; HR, 1.39; 95% CI, 1.23 to 1.57; P = 2.08 × 10-7), and rs7765004 at 6q21 (near MARCKS and HDAC2; HR, 1.38; 95% CI, 1.22 to 1.57; P = 7.09 × 10-7), although they did not reach conventional genome-wide significance (P = 5 × 10-8). Both rs7712513 (HR, 1.49; 95% CI, 1.29 to 1.72; P = 3.53 × 10-8) and rs7765004 (HR, 1.47; 95% CI, 1.27 to 1.71; P = 5.36 × 10-7) were also associated with OS. In exploratory analyses, a two-single nucleotide polymorphism risk score was highly predictive of EFS (P = 1.78 × 10-12) and was independent of treatment, IPI, and cell-of-origin classification. Conclusion Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with EFS and OS in patients with diffuse large B-cell lymphoma treated with immunochemotherapy, suggesting novel biology and the potential contribution of host genetics to the prognosis of this aggressive malignancy.

AB - Purpose We performed a multistage genome-wide association study to identify inherited genetic variants that predict outcome in diffuse large B-cell lymphoma patients treated with immunochemotherapy. Methods We conducted a meta-analysis of two genome-wide association study data sets, one from the LNH2003B trial (N = 540), a prospective clinical trial from the Lymphoma Study Association, and the other from the Molecular Epidemiology Resource study (N = 312), a prospective observational study from the University of Iowa-Mayo Clinic Lymphoma Specialized Program of Research Excellence. Top single nucleotide polymorphisms were then genotyped in independent cohorts of patients from the Specialized Program of Research Excellence (N = 391) and the Groupe Ouest-Est des Leucémies Aiguës et Maladies du Sang (GOELAMS) -075 randomized trial (N = 294). We calculated the hazard ratios (HRs) and 95% CIs for event-free survival (EFS) and overall survival (OS) using a log-additive genetic model with adjustment for age, sex, and age-adjusted International Prognostic Index. Results In a meta-analysis of the four studies, the top loci for EFS were marked by rs7712513 at 5q23.2 (near SNX2 and SNCAIP; HR, 1.39; 95% CI, 1.23 to 1.57; P = 2.08 × 10-7), and rs7765004 at 6q21 (near MARCKS and HDAC2; HR, 1.38; 95% CI, 1.22 to 1.57; P = 7.09 × 10-7), although they did not reach conventional genome-wide significance (P = 5 × 10-8). Both rs7712513 (HR, 1.49; 95% CI, 1.29 to 1.72; P = 3.53 × 10-8) and rs7765004 (HR, 1.47; 95% CI, 1.27 to 1.71; P = 5.36 × 10-7) were also associated with OS. In exploratory analyses, a two-single nucleotide polymorphism risk score was highly predictive of EFS (P = 1.78 × 10-12) and was independent of treatment, IPI, and cell-of-origin classification. Conclusion Our study provides encouraging evidence for associations between loci at 5q23.2 and 6q21 with EFS and OS in patients with diffuse large B-cell lymphoma treated with immunochemotherapy, suggesting novel biology and the potential contribution of host genetics to the prognosis of this aggressive malignancy.

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