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Haematologica. 2020 Jan 31;105(2):424-434. doi: 10.3324/haematol.2018.214122. Print 2020.

MYD88 mutations identify a molecular subgroup of diffuse large B-cell lymphoma with an unfavorable prognosis.

Author information

1
Department of Hematology, Amsterdam University Medical Center, University of Amsterdam j.s.p.vermaat@lumc.nl.
2
Lymphoma and Myeloma Center Amsterdam-LYMMCARE, and Cancer Center Amsterdam (CCA), Amsterdam.
3
Department of Hematology, Leiden University Medical Center, Leiden.
4
Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden.
5
Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, Amsterdam.
6
Department of Pathology, Leiden University Medical Center, Leiden.
7
Department of Internal Medicine & Hematology, Onze Lieve Vrouwe Gasthuis, Amsterdam.
8
Department of Pathology, Onze Lieve Vrouwe Gasthuis, Amsterdam.
9
Department of Internal Medicine & Hematology, Albert Schweitzer Hospital, Dordrecht.
10
Department of Internal Medicine & Hematology, Tergooi Hospital, Hilversum.
11
Department of Hematology, Amsterdam University Medical Center, University of Amsterdam.
12
Department of Internal Medicine & Hematology, Deventer Hospital, Deventer.
13
Department of Internal Medicine & Hematology, Waterland Hospital, Purmerend.
14
Department of Medical Oncology & Hematology, Antoni van Leeuwenhoekziekenhuis, Amsterdam.
15
Department 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 characterized by activating mutations in MYD88/CD79B We investigated whether MYD88/CD79B mutations could improve the classification and prognostication 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 fluorescence 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 rearrangements in 10.6%, 13.6%, and 20.3%, and EBV in 11.7% of DLBCL, respectively. Prominent mutual exclusivity between EBV positivity, rearrangements, 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 carrying ≥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 performance 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 diagnostics of DLBCL to optimize classification and prognostication, and to guide the development of improved treatment strategies.

PMID:
31123031
DOI:
10.3324/haematol.2018.214122
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