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Genome-Wide Association Study of Event-Free Survival in Diffuse Large B-Cell Lymphoma Treated With Immunochemotherapy
Hervé Ghesquieres1, Susan L Slager1, Fabrice Jardin1
1Hervé Ghesquieres, Universite Claude Bernard Lyon 1, Centre Leon Berard; Amelie S. Veron and David G. Cox, L'Institut National de la Santé et de la Recherche Médicale (INSERM) U1052, Cancer Research Center of Lyon, Centre Leon Berard, Lyon; Hervé Ghesquieres and Gilles A. Salles, Faculté de Médecine Lyon-Sud; Gilles A. Salles, Universite Claude Bernard Lyon 1, Centre Hospitalier Lyon Sud, Hospices Civils de Lyon, Pierre-Bénite; Fabrice Jardin, Sylvain Mareschal, and Herve Tilly, INSERM U918, Centre Henri Becquerel, Rouen; Thierry Fest, INSERM U917, Université de Rennes 1, Hopital Pontchaillou; Thierry Lamy, Université de Rennes 1, Hopital Pontchaillou, Rennes; Marie C. Bene, Centre Hospitalier Universitaire Nantes, Nantes; Corinne Haioun, Hospital Henri Mondor, Assistance Publique-Hôpitaux de Paris (AP-HP) and University Paris Est, Créteil; Thierry Jo Molina, Universite Paris Descartes, AP-HP, Hôpital Necker, Paris; Noel Milpied, University Hospital and University of Bordeaux, Bordeaux, France; Hervé Ghesquieres, Susan L. Slager, Matthew J. Maurer, Thomas M. Habermann, Anne J. Novak, Stephen M. Ansell, Thomas E. Witzig, Andrew L. Feldman, Ahmet Dogan, Julie M. Cunningham, Curtis L. Olswold, and James R. Cerhan, Mayo Clinic, Rochester, MN; Yan W. Asmann, Mayo Clinic, Jacksonville, FL; and George J. Weiner and Brian K. Link, University of Iowa, Iowa City, IA.
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.
