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Somatic mutations in DLBCL
impact of BCL2 SNV, although the negative prognostic effect of BCL2 SNV among patients without BCL2 translo- cations may point to an independent biological role for these alterations. BCL2 translocations were significantly enriched within the GCB subtype and were associated with shorter PFS within this subtype. BCL2 translocations were associated with high levels of BCL2 mRNA and pro- tein expression, both of which have been shown to be associated with an adverse prognosis in DLBCL, inde- pendent of COO and IPI, including in the GOYA study.24 Our data suggest that pharmacological inhibition of the BCL2 protein could be a promising treatment strategy in a subset of DLBCL patients. Venetoclax, a highly specific BCL2 inhibitor,25 is currently being tested in clinical trials in patients with newly diagnosed DLBCL; however, the subpopulation of DLBCL patients who could benefit from venetoclax needs to be defined.
Given the molecular uniqueness and prognostic value of the particular COO subtypes, we aimed to analyze the prognostic impact of genetic alterations within these sub- types. The only genetic alteration significantly associated
with shorter PFS within the GCB subtype was BCL2 translocation. None of the tested genetic alterations were significantly associated with outcome within the prognos- tically-inferior ABC subtype, supporting the strong prog- nostic significance of COO assessed by gene expression profiling.
In this study, we observed prognostic trends in several genes, including TP53, CREBBP and CDKN2A, but none met our thresholds for significance. There are several potential explanations for this observation. First, in the current study we used robust statistical methods with strict pre-defined criteria for significance to test the asso- ciation of particular gene alterations with clinical out- comes. Second, only truncating/frameshift mutations and previously reported loss-of-function mutations were included in this study. Alteration of several genes, such as CREBBP and TP53, were associated with shorter PFS in our study, in the absence of multiple testing correction.
When validating the genomic risk model from Reddy et al.,19 although the model was prognostic in our population when stratified into high- and low-risk groups (HR: 0.61;
CD
B
4-way P=0.94
EZB-like vs. other GCB P=0.023
G2/3/5 vs. G0/1/4:
P=0.0033
Figure 5. Diffuse large B-cell lymphoma (DLBCL) mutational subset validation. (A) Prevalence and (B) association of Schmitz et al.8 classifications with progression- free survival (PFS). Schmitz clusters were approximated using the seed mutations: EZB - EZH2 or BCL2; BN2 - BCL6 or NOTCH2; N1 - NOTCH1; MCD - MYD88, L265P or CD79B; Multi: multiple seed mutations from more than one cluster. (C) Chapuy et al.9 clusters were approximated by application of non-negative matrix factoriza- tion (NMF) to the GOYA Foundation Medicine Incorporated (FMI) dataset and selecting five clusters (G1-G5). Mutations with significant enrichment in one or more clusters are shown. (D) Association between NMF clusters and PFS. ABC: activated B-cell-like; alt: alteration; CNA: copy number abnormality; COO: cell-of-origin; GCB: germinal center B-cell-like; HR: hazard ratio; SNV: single nucleotide variant.
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