Follicular lymphoma t(14;18)-negative is genetically a heterogeneous disease

Abstract

Fifty-five cases of t(14;18)− follicular lymphoma (FL) were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)− FL predominated in women (M/F 1:2); patients often presented during early clinical stages (71%), and had excellent prognoses. Overall, t(14;18)− FL displayed CN alterations (CNAs) and gene mutations carried by conventional t(14;18)+ FL (cFL), but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%), and KMT2D (27%). t(14;18)− FL showed significantly more STAT6 mutations and lacked MYD88, NOTCH2, MEF2B, and MAP2K1 mutations compared with cFL, nodal marginal zone lymphoma (NMZL), and pediatric-type FL (PTFL). We identified 2 molecular clusters. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (96%) and frequent mutations in epigenetic regulators, with recurrent loss of 6q21-24 sharing many features with cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (65%). These 2 molecular clusters did not distinguish cases by inguinal localization, growth pattern, or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10 of 45 (22%) cases and did not cluster together. Cases with predominantly inguinal presentation (20 of 50; 40%) had a higher frequency of diffuse growth pattern, STAT6 mutations, CD23 expression, and a lower number of CNAs, in comparison with noninguinal cases (5.1 vs 9.1 alterations per case; P < .05). STAT6 mutations showed a positive correlation with CD23 expression (P < .001). In summary, t(14;18)− FL is genetically a heterogeneous disorder with features that differ from cFL, NMZL, and PTFL.

An immunogenic first-in-human immune modulatory vaccine with PD-L1 and PD-L2 peptides is feasible and shows early signs of efficacy in follicular lymphoma

“…T(14;18)-negative cases have distinct genetic and molecular expression patterns, but in general, they do not seem to differ in regard to prognosis and response to established treatments. 42,43 However, we cannot say if these differences influence the more intricate mode of action of cancer vaccines in comparison to chemotherapy. As our last case we found a significant reduction in circulating tumor DNA in Pt6.…”

Mutational landscape of high-grade B-cell lymphoma with <i>MYC-</i>, <i>BCL2</i> and/or <i>BCL6</i> rearrangements characterized by whole-exome sequencing

“…Of note, these findings fundamentally dispute the combined characterization in the current WHO classification, despite several shared clinical aspects common to all subtypes of HGBL-DH/TH (1, 2). Beyond de novo DLBCL with BCL6 rearrangement, potential alternative explanations for this phenomenon include both clonal evolution and subsequent aggressive transformation from rare cases of BCL6 rearranged marginal zone lymphomas alongside BCL2 non-rearranged/BCL6 rearranged FL, which were previously shown to be characterized by a heterogenous mutational landscape (45,46). From our data, we further deduce an intermediate role for HGBL-TH, which may indicate two divergent paths of clonal evolution originating from a BCL2 or a BCL6 driven disease with subsequent acquisition of the alternative rearrangement.…”

Prognostic impact of nutritional and inflammation-based risk scores in follicular lymphoma in the era of anti-CD20 targeted treatment strategies

“…Recently, alterations in EZH2 gene locus could be identified as driver mutations harboring the capability to guide therapeutic decision making in advanced stage FL (Jurinovic et al 2019;Szumera-CieCkiewicz et al 2020). Comprehensive genomic profiling revealed distinct heterogeneity in FL with or without the genetic hallmark of FL represented by the chromosomal translocation t(14;18)(q32;q21), which leads to an overexpression of the BCL-2 protein (Kretzmer et al 2015;Nann et al 2020;Qu et al 2019;Stevens et al 2017).…”