Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis

Author:

Broséus JulienORCID,Hergalant SébastienORCID,Vogt JuliaORCID,Tausch Eugen,Kreuz Markus,Mottok Anja,Schneider Christof,Dartigeas Caroline,Roos-Weil Damien,Quinquenel Anne,Moulin Charline,Ott German,Blanchet OdileORCID,Tomowiak CécileORCID,Lazarian Grégory,Rouyer Pierre,Chteinberg Emil,Bernhart Stephan H.,Tournilhac Olivier,Gauchotte Guillaume,Lomazzi Sandra,Chapiro EliseORCID,Nguyen-Khac FlorenceORCID,Chery Céline,Davi Frédéric,Hunault Mathilde,Houlgatte Rémi,Rosenwald Andreas,Delmer AlainORCID,Meyre David,Béné Marie-ChristineORCID,Thieblemont Catherine,Lichter Peter,Ammerpohl Ole,Guéant Jean-LouisORCID,Bernhart Stephan,Guièze Romain,Martin-Subero José IgnacioORCID,Cymbalista Florence,Feugier Pierre,Siebert Reiner,Stilgenbauer StephanORCID,

Abstract

AbstractRichter syndrome (RS) is the transformation of chronic lymphocytic leukemia (CLL) into aggressive lymphoma, most commonly diffuse large B-cell lymphoma (DLBCL). We characterize 58 primary human RS samples by genome-wide DNA methylation and whole-transcriptome profiling. Our comprehensive approach determines RS DNA methylation profile and unravels a CLL epigenetic imprint, allowing CLL-RS clonal relationship assessment without the need of the initial CLL tumor DNA. DNA methylation-and transcriptomic-based classifiers were developed, and testing on landmark DLBCL datasets identifies a poor-prognosis, activated B-cell-like DLBCL subset in 111/1772 samples. The classification robustly identifies phenotypes very similar to RS with a specific genomic profile, accounting for 4.3-8.3% of de novo DLBCLs. In this work, RS multi-omics characterization determines oncogenic mechanisms, establishes a surrogate marker for CLL-RS clonal relationship, and provides a clinically relevant classifier for a subset of primary “RS-type DLBCL” with unfavorable prognosis.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

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