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 W.
AU - Maurer, Matthew J.
AU - Fest, Thierry
AU - Habermann, Thomas M.
AU - Bene, Marie C.
AU - Novak, Anne J.
AU - Mareschal, Sylvain
AU - Haioun, Corinne
AU - Lamy, Thierry
AU - Ansell, Stephen M.
AU - Tilly, Herve
AU - Witzig, Thomas E.
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.
N1 - Publisher Copyright:
© 2015 American Society of Clinical Oncology. All rights reserved.
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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U2 - 10.1200/JCO.2014.60.2573
DO - 10.1200/JCO.2014.60.2573
M3 - Article
C2 - 26460308
AN - SCOPUS:84948449471
SN - 0732-183X
VL - 33
SP - 3930
EP - 3937
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 33
ER -