Distinct genetic changes reveal evolutionary history and heterogeneous molecular grade of DLBCL with MYC/BCL2 double-hit

Abstract

Using a Burkitt lymphoma-like gene expression signature, we recently defined a high-risk molecular high-grade (MHG) group mainly within germinal centre B-cell like diffuse large B-cell lymphomas (GCB-DLBCL), which was enriched for MYC/BCL2 double-hit (MYC/BCL2-DH). The genetic basis underlying MHG-DLBCL and their aggressive clinical behaviour remain unknown. We investigated 697 cases of DLBCL, particularly those with MYC/BCL2-DH (n = 62) by targeted sequencing and gene expression profiling. We showed that DLBCL with MYC/BCL2-DH, and those with BCL2 translocation, harbour the characteristic mutation signatures that are associated with follicular lymphoma and its high-grade transformation. We identified frequent MYC hotspot mutations that affect the phosphorylation site (T58) and its adjacent amino acids, which are important for MYC protein degradation. These MYC mutations were seen in a subset of cases with MYC translocation, but predominantly in those of MHG. The mutations were more frequent in double-hit lymphomas with IG as the MYC translocation partner, and were associated with higher MYC protein expression and poor patient survival. DLBCL with MYC/BCL2-DH and those with BCL2 translocation alone are most likely derived from follicular lymphoma or its precursor lesion, and acquisition of MYC pathogenic mutations may augment MYC function, resulting in aggressive clinical behaviour.

Genetic and evolutionary patterns of treatment resistance in relapsed B-cell lymphoma

“…Further evidence supporting this possibility has recently been gleaned through the genetic analysis of DLBCLs with MYC and BCL2 translocations. 46 In contrast to these early mutations, MS4A1 mutations are rare in untreated DLBCL and were generally undetectable prior to therapy. Our data indicate that these mutations directly contribute to rituximab resistance, resulting in rapid clonal selection and expansion in the presence of rituximabcontaining therapy.…”

Application of the LymphGen classification tool to 928 clinically and genetically‐characterised cases of diffuse large B cell lymphoma (DLBCL)

“…The LymphGen classifier suggests use of gene expression to identify a MYC‐driven subgroup of the EZB cluster. Since gene expression was not available for every patient, and in an attempt to probe the utility of a mutation‐only strategy, we took advantage of a recent observation that MYC mutations at codons 57–60 associate strongly with MYC ‐rearranged or MHG DLBCL 6,8 . We used the presence of these mutations to define a MYC‐driven subgroup of the EZB cluster.…”

Primary cardiac CD5-positive diffuse large B-cell lymphoma:A case report and review of literature

“…Patients with DLBCL demonstrating high myc and bcl-2 protein expression by IHC, regardless of status of myc or bcl-2 gene rearrangements, have been shown to have a poorer prognosis. High-grade B-cell lymphomas with both myc and bcl-2 gene rearrangements or double-hit lymphomas are known to have an extremely poor prognosis [10,11] . The median survival time was less than 2 years [12] .…”