Prognostic impact of somatic mutations in diffuse large B-cell lymphoma and relationship to cell-of-origin: data from the phase III GOYA study

Christopher R Bolen, Magdalena Klanova, Marek Trneny, Laurie H Sehn, Jie He, Jing Tong, Joseph N Paulson, Eugene Kim, Umberto Vitolo, Alice Di Rocco, Günter Fingerle-Rowson, Tina Nielsen, Georg Lenz, Mikkel Z Oestergaard, Christopher R Bolen, Magdalena Klanova, Marek Trneny, Laurie H Sehn, Jie He, Jing Tong, Joseph N Paulson, Eugene Kim, Umberto Vitolo, Alice Di Rocco, Günter Fingerle-Rowson, Tina Nielsen, Georg Lenz, Mikkel Z Oestergaard

Abstract

Diffuse large B-cell lymphoma represents a biologically and clinically heterogeneous diagnostic category with well-defined cell-of-origin subtypes. Using data from the GOYA study (NCT01287741), we characterized the mutational profile of diffuse large B-cell lymphoma and evaluated the prognostic impact of somatic mutations in relation to cell-of-origin. Targeted DNA next-generation sequencing was performed in 499 formalin-fixed paraffin-embedded tissue biopsies from previously untreated patients. Prevalence of genetic alterations/mutations was examined. Multivariate Cox regression was used to evaluate the prognostic effect of individual genomic alterations. Of 465 genes analyzed, 59 were identified with mutations occurring in at least 10 of 499 patients (≥2% prevalence); 334 additional genes had mutations occurring in ≥1 patient. Single nucleotide variants were the most common mutation type. On multivariate analysis, BCL2 alterations were most strongly associated with shorter progression-free survival (multivariate hazard ratio: 2.6; 95% confidence interval: 1.6 to 4.2). BCL2 alterations were detected in 102 of 499 patients; 92 had BCL2 translocations, 90% of whom had germinal center B-cell-like diffuse large B-cell lymphoma. BCL2 alterations were also significantly correlated with BCL2 gene and protein expression levels. Validation of published mutational subsets revealed consistent patterns of co-occurrence, but no consistent prognostic differences between subsets. Our data confirm the molecular heterogeneity of diffuse large B-cell lymphoma, with potential treatment targets occurring in distinct cell-of-origin subtypes. clinicaltrials.gov identifier: NCT01287741.

Figures

Figure 1.
Figure 1.
Frequently observed gene alterations in patients with diffuse large B-cell lymphoma (DLBCL) in the GOYA trial (clinicaltrials.gov identifier: NCT01287741). (A) Most frequently (≥2% of cases) observed gene alterations: single nucleotide variant (SNV), amplifications and deletions. (B) Genes with significant differences in mutation rates* between the activated B-cell-like (ABC) and germinal center B-cell-like (GCB) DLBCL subtypes. (C) Frequency of BCL2 and CDKN2A alterations in the ABC and GCB DLBCL subtypes. *False discovery rate (FDR) <0.05. CNA: copy number abnormality; trans: translocation.
Figure 2.
Figure 2.
Association between BCL2 gene alterations and progression-free survival (PFS) in diffuse large B-cell lymphoma (DLBCL). (A) All BCL2 alterations. (B) BCL2 single nucleotide variant. (C) BCL2 translocations. CI: confidence interval; FDR: false discovery rate; HR: hazard ratio; MUT: mutant; WT: wild-type.
Figure 3.
Figure 3.
BCL2 alterations according to cell-of-origin (COO) subtype. *Germinal center B-cell-like (GCB), 31%; unclassified, 5.1%; activated B-cell-like (ABC), 0.8%. †GCB, 11%; unclassified, 0%; ABC, 4.5%. ‡GCB, 1.5%; unclassified, 2.6%; ABC, 6.8%. amp: amplification; NA: not available; SNV: single nucleotide variant; trans: translocation.
Figure 4.
Figure 4.
(A) Distribution of risk scores using the applied Reddy et al.19 prognostic model, and (B) progression- free survival (PFS) by risk group (n=443). int: intermediate.
Figure 5.
Figure 5.
Diffuse large B-cell lymphoma (DLBCL) mutational subset validation. (A) Prevalence and (B) association of Schmitz et al.8 classifications with progressionfree 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 factorization (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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