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.

1st Department of Medicine Charles University General Hospital Prague Czech Republic

A O Universitaria Città della Salute e della Scienza di Torino Ematologia Torino Italy

Bioinformatics and Computational Biology Genentech Inc South San Francisco CA USA

British Columbia Cancer Centre for Lymphoid Cancer Vancouver Canada

Department of Biostatistics Product Development Genentech Inc South San Francisco CA USA

Department of Cellular Biotechnologies and Hematology Sapienza University Rome Italy

Department of Medicine A Hematology Oncology and Pneumology University Hospital Muenster Muenster

Foundation Medicine Inc Cambridge MA USA

Oncology Biomarker Development F Hoffmann La Roche Ltd Basel Switzerland

Pharma Development Clinical Oncology F Hoffmann La Roche Ltd Basel Switzerland

Haematologica. 2020 Jun 05;105(9):2194-2196. doi: 10.3324/haematol.2020.255448. PubMed

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ClinicalTrials.gov
NCT01287741