Similar clinical features in follicular lymphomas with and without breaks in the BCL2 locus

Abstract

Approximately 15% of follicular lymphomas (FLs) lack breaks in the BCL2 locus. The aim of this study was to better define molecular and clinical features of BCL2-breakpoint/t(14;18)-negative FLs. We studied the presence of BCL2, BCL6 and MYC breaks by fluorescence in situ hybridization and the expression of BCL2, MUM1, CD10, P53 and Ki67 in large clinical trial cohorts of 540 advanced-stage FL cases and 116 early-stage disease FL patients treated with chemotherapy regimens and radiation, respectively. A total of 86% and 53% of advanced- and early-stage FLs were BCL2-breakpoint-positive, respectively. BCL2 was expressed in almost all FLs with BCL2 break and also in 86% and 69% of BCL2-breakpoint-negative advanced- and early-stage FLs, respectively. CD10 expression was significantly reduced in BCL2-breakpoint-negative FLs of all stages and MUM1 and Ki67 expression were significantly increased in BCL2-break-negative early-stage FLs. Patient characteristics did not differ between FLs with and without BCL2 breaks and neither did survival times in advanced-stage FLs. These results suggest that the molecular profile differs to some extent between FLs with and without BCL2 breaks and support the notion that FLs with and without BCL2 breaks belong to the same lymphoma entity.

Comparative analysis between RQ‐PCR and digital droplet PCR of BCL2/IGH gene rearrangement in the peripheral blood and bone marrow of early stage follicular lymphoma

“…The presence of lymphoma cells carrying a MBR, mcr or a minor BCL2 rearrangement in the PB and/or BM was determined by qualitative PCR in the majority of patients (71·6%), who were defined as stage I/II FL according to the conventional staging procedures, including a negative BM histology. This figure is somewhat higher than what expected (Leich et al , ), but it should be underlined that 6 cases (9%) were identified by the analysis of minor and newly defined BCL2 rearrangements, whilst the proportion of MBR+ and mcr+ cases (63%) is comparable with the one (66%) reported in our original experience (Pulsoni et al , ), confirming the limits of the standard staging procedures.…”

“…In order to understand the pathogenesis of early stage FL, we certainly recognize the value of better characterizing early stage FL without t(14;18) compared to those with t(14;18). Leich et al () reported that, at variance from advanced FL, about 50% of early stage FL cases do not show a t(14;18) in the LN by fluorescence in situ hybridisation (FISH), but the over‐expression of the BCL2 protein is still present in 69% of them. The molecular mechanisms underlying these cases certainly need to be elucidated.…”

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

“…In fact, MYC/BCL6-DH DLBCL are highly heterogeneous in their molecular subtypes, indicating their diverse COO, notwithstanding the high prevalence of NOTCH2 mutations [23,24]. BCL6 translocation is recurrently seen in both follicular and marginal zone lymphoma [56][57][58][59]. It would be interesting to explore whether MYC/BCL6-DH DLBCL also result from high-grade transformation of a low-grade lesion such as follicular or marginal zone B-cell lymphoma or their precursor lesions, and their heterogeneous molecular subtypes reflect their inherent features from their derived low-grade lesion.…”

Pathogenesis and therapeutic targeting of aberrant MYC expression in haematological cancers

“…MYC translocations can also be found in transformed or high‐grade follicular lymphoma (FL) (Pasqualucci et al , ), indicating a more aggressive phenotype with adverse prognosis, similar to the aforementioned DHL (Koch et al , ). However, in a recent study including high‐ and low grade FL, MYC breaks were also found in 6·3% of low‐grade FL, but the fraction of cells affected by this alteration was low compared to high‐grade FL with MYC translocations (Leich et al , ). These data reflect the complexity in the continuum of transformation of FL into a more aggressive disease, where the role of MYC activation is not fully understood.…”