4.8 Article

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

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NATURE COMMUNICATIONS
卷 14, 期 1, 页码 -

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NATURE PORTFOLIO
DOI: 10.1038/s41467-022-34642-6

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This study characterizes the DNA methylation and transcriptomic profiles of Richter syndrome (RS), and develops classifiers for RS-type de novo diffuse large B-cell lymphomas (DLBCLs).
Richter syndrome (RS) is the transformation of chronic lymphocytic leukaemia (CLL) into aggressive lymphoma, in most cases diffuse large B-cell lymphoma (DLBCL). Here, the authors characterize the DNA methylation and transcriptomic profiles of RS samples, find a clonally-related CLL epigenetic imprint, and develop classifiers for RS-type de novo DLBCLs. 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.

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