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Haematologica. 2019 May 23. pii: haematol.2018.214122. doi: 10.3324/haematol.2018.214122. [Epub ahead of print]

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

Author information

1
Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands; j.s.p.vermaat@lumc.nl.
2
Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
3
Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands.
4
Department of Pathology, Amsterdam University Medical Center,University of Amsterdam,The Netherlands.
5
Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands.
6
Department of Internal Medicine and Hematology,Onze Lieve Vrouwe Gasthuis,Amsterdam, The Netherlands.
7
Department of Pathology and Hematology,Onze Lieve Vrouwe Gasthuis,Amsterdam, The Netherlands.
8
Department of Internal Medicine and Hematology,Albert Schweitzer Hospital, Dordrecht, The Netherland.
9
Department of Internal Medicine and Hematology, Tergooi Hospital, Hilversum, The Netherlands.
10
Department of Hematology,Amsterdam University Medical Center,University of Amsterdam,The Netherlands.
11
Department of Internal Medicine and Hematology, Waterland Hospital, Purmerend, The Netherlands.
12
Department of Medical Oncology and Hematology, Antoni van Leeuwenhoekziekenhuis, Amsterdam.
13
Department of Hematology, University Medical Center Groningen, Groningen, The Netherlands.
14
Amsterdam University Medical Center, University of Amsterdam, The Netherlands.
15
Academic Medical Center and University of Amsterdam, The Netherlands.

Abstract

The 2016 WHO classification defines diffuse large B-cell lymphoma subtypes based on EBV infection and oncogenic rearrangements of MYC/BCL2/BCL6 as drivers of lymphomagenesis. A subset of diffuse large B-cell lymphoma, however, is characterized by activating mutations in MYD88/CD79B. We investigated whether MYD88/CD79B mutations could improve the classification and prognostication of diffuse large B-cell lymphomas. In 250 primary diffuse large B-cell lymphomas, MYD88/CD79B mutations were identified by allele-specific PCR or next-generation-sequencing, MYC/BCL2/BCL6 rearrangements were analyzed by FISH, and EBV was studied by EBER-ISH. Associations of molecular features with clinicopathologic characteristics, outcome, and prognosis according to International Prognostic Index 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 diffuse large B-cell lymphomas, respectively. Prominent mutual exclusivity between EBV positivity, rearrangements, and MYD88/CD79B mutations established the value of molecular markers for recognition of biologically distinct diffuse large B-cell lymphoma subtypes. MYD88-mutated diffuse large B-cell lymphoma had a significantly inferior 5-year overall survival than wild-type MYD88 diffuse large B-cell lymphoma (log-rank;P=0.019). Diffuse large B-cell lymphoma 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 International Prognostic Index. This study demonstrates the clinical utility of defining MYD88-mutated diffuse large B-cell lymphoma as a distinct molecular subtype with adverse prognosis. Our data call for sequence analysis of MYD88 in routine diagnostics of diffuse large B-cell lymphoma to optimize classification and prognostication, and to guide the development of improved treatment strategies.

KEYWORDS:

Aggressive Non-Hodgkin's Lymphoma; Clinical and Molecular Epidemiology; Cytogenetics and Molecular Genetics; MYD88; prognosis

PMID:
31123031
DOI:
10.3324/haematol.2018.214122
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