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Ferrata Storti Foundation
Haematologica 2020 Volume 105(9):2298-2307
Non-Hodgkin Lymphoma
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,1* Magdalena Klanova,2,3,4* Marek Trnény,2
Laurie H. Sehn,5 Jie He,6 Jing Tong,6 Joseph N. Paulson,7 Eugene Kim,7
Umberto Vitolo,8 Alice Di Rocco,9 Günter Fingerle-Rowson,4 Tina Nielsen,4
Georg Lenz10 and Mikkel Z. Oestergaard11
1
Bioinformatics and Computational Biology, Genentech Inc., South San Francisco, CA,
USA; 21st Department of Medicine, Charles University General Hospital, Prague, Czech Republic; 3Institute of Pathological Physiology, 1st Faculty of Medicine, Charles University, Prague, Czech Republic; 4Pharma Development Clinical Oncology, F. Hoffmann-La Roche Ltd., Basel, Switzerland; 5British Columbia Cancer Centre for Lymphoid Cancer, Vancouver, British Columbia, Canada; 6Foundation Medicine Inc., Cambridge, MA, USA; 7Department of Biostatistics, Product Development, Genentech Inc., South San Francisco, CA, USA; 8A.O. Universitaria Città della Salute e della Scienza di Torino, Dipartimento di Ematologia, Torino, Italy; 9Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy; 10Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Münster, Germany and 11Oncology Biomarker Development, F. Hoffmann-La Roche Ltd. Basel, Switzerland
ABSTRACT
Diffuse large B-cell lymphoma (DLBCL) represents a biologically and clinically heterogeneous diagnostic category with well-defined cell- of-origin (COO) subtypes. Using data from the GOYA study (clini- caltrials.gov identifier: NCT01287741), we characterized the mutational pro- file of DLBCL and evaluated the prognostic impact of somatic mutations in relation to COO. Targeted DNA next-generation sequencing was per- formed in 499 formalin-fixed paraffin-embedded tissue biopsies from pre- viously 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 mul- tivariate analysis, BCL2 alterations were most strongly associated with shorter progression-free survival (multivariate hazard ratio: 2.6; 95% confi- dence interval: 1.6-4.2). BCL2 alterations were detected in 102 of 499 patients; 92 had BCL2 translocations, 90% of whom had germinal center B-cell-like DLBCL. BCL2 alterations were also significantly correlated with BCL2 gene and protein expression levels. Validation of published mutation- al subsets revealed consistent patterns of co-occurrence, but no consistent prognostic differences between subsets. Our data confirm the molecular heterogeneity of DLBCL, with potential treatment targets occurring in dis- tinct COO subtypes.
Introduction
Diffuse large B-cell lymphoma (DLBCL) represents a biologically and clinically heterogeneous diagnostic category. Distinct DLBCL cell-of-origin (COO) subtypes, arising from different stages of normal B-cell development and with different prog- nostic outcomes, were identified almost two decades ago.1-3 Several studies have since described the landscape of recurrent somatic mutations in DLBCL and demonstrated the molecular uniqueness of the distinct COO subtypes, and recent studies have suggested clinically relevant genetic subgroups exist within each sub-
*CRB and MK contributed equally as co-first authors.
Correspondence:
CHRISTOPHER R. BOLEN
bolen.christopher@gene.com
Received: June 14, 2019. Accepted: November 14, 2019. Pre-published: November 14, 2019.
doi:10.3324/haematol.2019.227892 ©2020 Ferrata Storti Foundation
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