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.

Figure 1

Frequency of mutations at diagnosis (WM) and transformation (DLBCL). Comparison of the median number of mutations of the four patients at diagnosis (n=21) and upon transformation (n=85).

Figure 2

Representation of the total number of alterations at each moment (diagnosis, progression and transformation) versus the time to transformation. Patients 1 and 3 presented the fastest transformation (~3 years) and the highest frequency of variants (165 and 98, respectively). Patient 2 transformed in 5 years and had 72 mutations. Patient 4 took 13 years to transform and acquired only 49 alterations.

Figure 3

VAF of common mutations at diagnosis, progression and transformation for each patient. The percentage of tumor cells affected by a mutation decreased from diagnosis to transformation in most of the cases.

Figure 4

Evolution of WM in patient 2. This patient was diagnosed with WM in 2010 and transformed to DLBCL in 2015, with a symptomatic progression in 2013 before the transformation. We observed 35 mutations at diagnosis, 47 at relapse and 72 at transformation, including 29 alterations that were conserved at the times of the three events. The PPM1D, SBF2, TRAPPC9, TRPM7 and WT1 genes were mutated either at progression or transformation. By contrast, the two mutations found in TP53 were seen at relapse but were lost by the time of transformation. This implies that the transformed final clone did not evolve from the same subclone as was responsible for progression, but from a previous one that would not yet have acquired the TP53 mutations (among others).