From Waldenström’s macroglobulinemia to aggressive diffuse large B-cell lymphoma: a whole-exome analysis of abnormalities leading to transformation

Abstract

Transformation of Waldenström’s macroglobulinemia (WM) to diffuse large B-cell lymphoma (DLBCL) occurs in up to 10% of patients and is associated with an adverse outcome. Here we performed the first whole-exome sequencing study of WM patients who evolved to DLBCL and report the genetic alterations that may drive this process. Our results demonstrate that transformation depends on the frequency and specificity of acquired variants, rather than on the duration of its evolution. We did not find a common pattern of mutations at diagnosis or transformation; however, there were certain abnormalities that were present in a high proportion of clonal tumor cells and conserved during this transition, suggesting that they have a key role as early drivers. In addition, recurrent mutations gained in some genes at transformation (for example, PIM1, FRYL and HNF1B) represent cooperating events in the selection of the clones responsible for disease progression. Detailed comparison reveals the gene abnormalities at diagnosis and transformation to be consistent with a branching model of evolution. Finally, the frequent mutation observed in the CD79B gene in this specific subset of patients implies that it is a potential biomarker predicting transformation in WM.

Biological Features and Prognostic Impact of Bone Marrow Infiltration in Patients with Diffuse Large B-cell Lymphoma

“…Interestingly, three out of the five discordant BM cases with a CLL phenotype were not clonally related. Genomic analysis may be necessary to determine whether the mechanisms involved in transformation in this group of patients match those observed in a series of documented high-grade transformations from the different indolent lymphomas [25][26][27][28].…”

Clinical Reasoning: Multifocal neuropathies in a patient with Waldenstrom macroglobulinemia and prior borreliosis

“…About 10% of patients with low-grade lymphomas undergo transformation to diffuse large B-cell lymphoma (DLBCL). 6 Although uncommon, this diagnosis explains all of the patient's findings.…”

Lymphoplasmacytic lymphoma associated with diffuse large B-cell lymphoma: Progression or divergent evolution?

“…It is highly correlated to deletion of 17p and to cases with higher number of genetic alterations [33]. Interestingly, Jiménez C et al [26] identified p53 gene mutations by whole-exome sequencing studies in two patients at transformation or at progression, but not by the time of disease transformation of this last patient. They suggested that the transformed final clone did not originate in the intermediate subclone responsible from progression, but from a previous minor subclone that only grew after progression.…”

“…at diagnosis, before treatment, during therapy and even 20 years after the initial diagnosis. Interestingly, this secondary DLBCL can be either clonally or not clonally related to the WM neoplasm [6][7][8]. These facts make the distinction between progression of a low-grade B-cell lymphoma and the development of a second primary aggressive tumor sometimes challenging.…”