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Non-Hodgkin Lymphoma
Ferrata Storti Foundation
Haematologica 2020 Volume 105(2):424-434
MYD88 mutations identify a molecular subgroup of diffuse large B-cell lymphoma with an unfavorable prognosis
Joost S. Vermaat,1,2,3 Sebastiaan F. Somers,3 Liesbeth C. de Wreede,4 Willem Kraan,2,5 Ruben A.L. de Groen,3 Anne M. R. Schrader,6
Emile D. Kerver,7 Cornelis G. Scheepstra,8 Henriëtte Berenschot,9
Wendy Deenik,10 Jurgen Wegman,1,11 Rianne Broers,12 Jan-Paul D. de Boer,13 Marcel Nijland,14 Tom van Wezel,6 Hendrik Veelken,3 Marcel Spaargaren,2,5 Arjen H. Cleven,6 Marie José Kersten1,2 and Steven T. Pals2,5
1Department of Hematology, Amsterdam University Medical Center, University of Amsterdam; 2Lymphoma and Myeloma Center Amsterdam-LYMMCARE, and Cancer Center Amsterdam (CCA), Amsterdam; 3Department of Hematology, Leiden University Medical Center, Leiden; 4Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden; 5Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam; 6Department of Pathology, Leiden University Medical Center, Leiden; 7Department of Internal Medicine & Hematology, Onze Lieve Vrouwe Gasthuis, Amsterdam; 8Department of Pathology, Onze Lieve Vrouwe Gasthuis, Amsterdam; 9Department of Internal Medicine & Hematology, Albert Schweitzer Hospital, Dordrecht; 10Department of Internal Medicine & Hematology, Tergooi Hospital, Hilversum; 11Department of Internal Medicine & Hematology, Deventer Hospital, Deventer; 12Department of Internal Medicine & Hematology, Waterland Hospital, Purmerend; 13Department of Medical Oncology & Hematology, Antoni van Leeuwenhoekziekenhuis, Amsterdam and 14Department of Hematology, University Medical Center Groningen, Groningen, the Netherlands
ABSTRACT
The 2016 World Health Organization classification defines diffuse large B-cell lymphoma (DLBCL) subtypes based on Epstein-Barr virus (EBV) infection and oncogenic rearrangements of MYC/BCL2/BCL6 as drivers of lymphomagenesis. A subset of DLBCL, however, is character- ized by activating mutations in MYD88/CD79B. We investigated whether MYD88/CD79B mutations could improve the classification and prognosti- cation of DLBCL. In 250 primary DLBCL, MYD88/CD79B mutations were identified by allele-specific polymerase chain reaction or next-generation- sequencing, MYC/BCL2/BCL6 rearrangements were analyzed by fluores- cence in situ hybridization, and EBV was studied by EBV-encoded RNA in situ hybridization. Associations of molecular features with clinicopathologic characteristics, outcome, and prognosis according to the International Prognostic Index (IPI) were investigated. MYD88 and CD79B mutations were identified in 29.6% and 12.3%, MYC, BCL2, and BCL6 rearrange- ments in 10.6%, 13.6%, and 20.3%, and EBV in 11.7% of DLBCL, respec- tively. Prominent mutual exclusivity between EBV positivity, rearrange- ments, and MYD88/CD79B mutations established the value of molecular markers for the recognition of biologically distinct DLBCL subtypes. MYD88-mutated DLBCL had a significantly inferior 5-year overall survival than wild-type MYD88 DLBCL (log-rank; P=0.019). DLBCL without any of the studied aberrations had superior overall survival compared to cases car- rying ≥1 aberrancy (log-rank; P=0.010). MYD88 mutations retained their adverse prognostic impact upon adjustment for other genetic and clinical variables by multivariable analysis and improved the prognostic perform- ance of the IPI. This study demonstrates the clinical utility of defining MYD88-mutated DLBCL as a distinct molecular subtype with adverse prognosis. Our data call for sequence analysis of MYD88 in routine diag- nostics of DLBCL to optimize classification and prognostication, and to guide the development of improved treatment strategies.
Correspondence:
JOOST S. VERMAAT
j.s.p.vermaat@lumc.nl
Received: December 24, 2018. Accepted: May 22, 2019. Pre-published: May 23, 2019.
doi:10.3324/haematol.2018.214122
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/105/2/424
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