Genomic profiling of Richter's syndrome: recurrent lesions and differences with de novo diffuse large B‐cell lymphomas

Abstract

Richter's syndrome (RS) represents the transformation of chronic lymphocytic leukaemia (CLL) to aggressive lymphoma and is mostly represented by diffuse large B-cell lymphoma (DLBCL), with a post-germinal centre (GC) phenotype, clonally related to the pre-existing CLL. RS has a very poor prognosis and its pathogenetic mechanisms are poorly understood. In order to gain additional hints in RS pathogenesis, we performed a genome-wide DNA profiling study of 13 RS phases and eight matched CLL phases using the Affymetrix Human Mapping 250K NspI SNP arrays. Individual genomic profiles were heterogeneous, with no individual lesions occurring in more than half of the cases. However, several observations suggest that MYC pathway might be involved in RS. The 13q13.3-qter region containing MIRHG1 (MIR-17-92), a cluster of microRNA interacting with c-MYC, was acquired at the time of transformation. The 13q gain was coupled with the gain of c-MYC and loss of TP53. Translocation of c-MYC was acquired at transformation in a fraction of cases and this event appeared mutually exclusive with gain of MIRHG1. MYCN, a c-MYC homologue, was also recurrently gained. By comparing RS with 48 de novo DLBCL, RS presented a significantly lower prevalence of deletions affecting the PRDM1 and TNFAIP3, genes on 6q, known to be associated with a post-GC phenotype. In conclusion, the genomic profile of RS seems to differ from what observed in de novo DLBCL and in other transformed DLBCL. Genomic lesions occurring in RS are heterogeneous suggesting the existence of different RS subsets, possibly due to different transforming mechanisms. A deregulation of MYC pathway might represent one of the main transformation events in the pathogenesis of a subset of RS clonally related to the previous CLL.

Cytogenetics and molecular cytogenetics in diffuse large B-cell lymphoma (DLBCL)

“…MIRHG1 is a group of microRNAs involved in lymphomagenesis through interaction with the MYC signaling pathway 29 participating in the pathogenesis of DLBCL. Genetic studies have confirmed that in more than 50% of RS cases, there is at least one chromosomal aberration leading to deregulation of the MYC signaling pathway 28 .…”

“…De novo DLBCL has a significantly different profile from the transformed form 28 . The relationship between pathogenesis of de novo DLBCL and RS DLBCL has not been explained but it is clear that deregulations of BCL2 and BCL6 are associated with de novo DLBCL (ref.…”

“…The relationship between pathogenesis of de novo DLBCL and RS DLBCL has not been explained but it is clear that deregulations of BCL2 and BCL6 are associated with de novo DLBCL (ref. 28 ). The transformation from CLL is evidenced by cytogenetic aberrations involving a gain of the 13q region (13q13.3qter), including the MIRHG1 locus 28 .…”

“…28 ). The transformation from CLL is evidenced by cytogenetic aberrations involving a gain of the 13q region (13q13.3qter), including the MIRHG1 locus 28 . MIRHG1 is a group of microRNAs involved in lymphomagenesis through interaction with the MYC signaling pathway 29 participating in the pathogenesis of DLBCL.…”

“…Apart from the MYC gene deregulation, other aberrations occur during RS, in particular deletion of the tumor suppressor gene TP53 and a gain of MYCN (ref. 28 ). The resources reporting cytogenetic aberrations occurring during the transformation period suggest that the prognosis of RS DLBCL is very poor, worse in de novo DLBCL (ref.…”