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 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.