Diffuse large B-cell lymphoma genetic classification by targeted sequencing and associations with immunochemotherapy-treated patients’ clinical outcome

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease whose prognosis is associated with clinical features, cell-of-origin and genetic aberrations. We examined whether genetic alterations of individual genes or genes clustered in pathways are associated with clinical outcome in R-CHOP-treated patients. We analyzed 84 diagnostic samples from patients with DLBCL treated with R-containing therapies by targeted massive sequencing. A genetic classification was derived from mutational data. Logistic regression and Kaplan–Meier analyses for survival and risk of relapse were performed. The most frequently mutated genes were IGLL5 (43%), KMT2D (33.3%), CREBBP (28.6%), PIM1 (26.2%), and CARD11 (22.6%). Mutations in CD79B, PRDM1, and NOTCH2 were associated with a higher risk of relapse after treatment, whereas patients with mutations in CD79B, ETS1, PRDM1, and TNFAIP3 had significantly shorter survival. Analyzing the impact of gene mutations on predefined gene sets related to lymphomagenesis revealed that mutations in genes involved in B-cell development, and BCR-PI3K and MAPK-ERK pathways are associated with significantly higher risk of relapse and/or shorter overall survival. We classified the samples into MCD, BN2, EZB, ST2, and N1 genetic subgroups, tested their clinical impact and found the EZB and ST2 subtypes to have a better clinical course and a lower risk of relapse. We propose a validated genetic DLBCL classifier based on an optimized panel of genes that could be used in pathology laboratories and eventually implemented as part of clinical routine.