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A. Vogelsberg et al.
Figure 2. Overview of clonality results, translocations and non-synonymous variants in in situ follicular neoplasia, follicular lymphoma and aggressive B-cell lym- phoma samples. Each column of the heatmap represents a sample with paired samples displayed next to each other. Rows represent an analysis or a gene. Genes are ordered from top to bottom according to the mutational frequency across all samples. Biopsy timing specifies the time period between the occurrence of the in situ follicular neoplasia (ISFN) and the diagnosis of aggressive B-cell lymphoma (BCL) in years (“y”), rounded to the nearest half year, with “syn” indicating a synchro- nous occurrence. In case 4, the assumption of branched evolution is based on a private 5’UTR mutation of BCL2 in the ISFN (mutation not shown). Concerning case 9, “Private and shared mutations” of BCL2 indicate that ISFN and follicular lymphoma (FL) exhibit a shared BCL2 mutation not present in the high-grade B-cell lym- phoma while a second BCL2 mutation was shared between all three lesions.
ISFN of case 6 harbored the highest number of private mutations, with a total of 13 different non-synonymous alterations of BCL2, KMT2D, CREBBP, GNA13, MEF2B, PIM1, TBL1XR1, and IGLL5, as well as six synonymous and 5’UTR variants of BCL2, of which only a single TBL1XR1 p.(L198*) mutation was shared with the clonal- ly related aggressive BCL.
Based on the distribution of private and shared variants, two different patterns of clonal evolution from ISFN to aggressive BCL could be reconstructed (Figure 3; Online Supplementary Figure S2). The most frequent scenario (cases 1, 2, 4, 5, 6, 7, 8, and 9) was that of branched evo- lution, where aggressive lymphoma, ISFN and, when present, FL evolved from a common progenitor but gained distinct private mutations (Figure 3A and B). In contrast, the available data indicate a linear evolution in cases 3 and 10, where the DLBCL shared all ISFN muta- tions but gained additional alterations (Figure 3C).
Discussion
In this study, we analyzed the clonal evolution of t(14;18)+ aggressive BCL from the earliest morphological- ly identifiable putative precursor lesion - ISFN, using paired samples of ISFN and DLBCL or HGBL with DH/TH, with and without FL as an intermediate step.
The clonal relationship of ISFN and aggressive BCL sam- ples was confirmed by either identical IGH and/or BCL2 rearrangements and/or the demonstration of shared somatic mutations in genes frequently affected in BCL of GC origin. This study demonstrates for the first time the evolution of “de novo” aggressive BCL from ISFN. Moreover, we identified different pathways of clonal evolution with an early branching pattern (early diver- gence) as the most frequent scenario.
The progression from ISFN to FL and the transforma- tion of FL to DLBCL or HGBL are well-established. Our study expands these observations and suggests that a direct evolution of t(14;18)+ aggressive BCL from ISFN is possible. This finding is not surprising, given the common presence of discordant (i.e., low-grade) bone marrow infiltration in de novo DLBCL and the occasional recur- rence of DLBCL as FL.26-29 As for any other neoplasm with a stepwise evolution, we cannot entirely exclude the presence of a clinically and morphologically undetected FL. However, given the fact that approximately 30% of de novo DLBCL carry a BCL2 translocation, t(14;18)+ DLBCL arising from ISFN without preceding FL could be a com- mon phenomenon.3,23 The more recent analyses of the molecular landscape of DLBCL also support this hypoth- esis of a shared progenitor population, since t(14;18)+ de novo DLBCL revealed a mutational signature very similar to FL.30,31 In ISFN and de novo DLBCL of case 5, we were
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haematologica | 2021; 106(10)