Molecular characterization of Richter syndrome identifies de novo diffuse large B-cell lymphomas with poor prognosis
Julien Broséus, Sébastien Hergalant, J. Vogt, Eugen Tausch, Markus Kreuz, Anja Mottok, Christof Schneider, Caroline Dartigeas, Damien Roos‐Weil, Anne Quinquenel, Charline Moulin, German Ott, Odile Blanchet, Cécile Tomowiak, Grégory Lazarian, Pierre Rouyer, Emil Chteinberg, Stephan Wolf, Olivier Tournilhac, Guillaume Gauchotte, Sandra Lomazzi, Élise Chapiro, Florence Nguyen‐Khac, Céline Chéry, Frédéric Davi, Mathilde Hunault, Rémi Houlgatte, Andreas Rosenwald, Alain Delmer, David Meyre, Marie C. Béné, Catherine Thiéblemont, Peter Lichter, Ole Ammerpohl, Jean‐Louis Guéant, Stephan Bernhart, Romain Guièze, José I. Martín‐Subero, Florence Cymbalista, Pierre Feugier, Reiner Siebert, Stephan Stilgenbauer
Abstract
Richter 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.