Genomic and epigenomic co-evolution in follicular lymphomas

Abstract

Follicular lymphoma (FL) with a t(14;18) is a B-cell neoplasm clinically characterized by multiple recurrencies. In order to investigate the clonal evolution of this lymphoma, we studied paired primary and relapse tumor samples from 33 patients with recurrent non-transformed t(14;18)-positive FL. We reconstructed phylogenetic trees of the evolution by taking advantage of the activation-induced cytidine deaminase (AID)-mediated somatic hypermutation (SHM) active in the germinal center reaction using sequences of the clonal VHDHJH rearrangements of the immunoglobulin heavy chain (IGH) locus. Mutational analysis of the IGH locus showed evidence for ongoing somatic mutation and for counter-selection of mutations affecting the BCR conformation during tumor evolution. We further followed evolutionary divergence by targeted sequencing of gene loci affected by aberrant SHM as well as of known driver genes of lymphomagenesis, and by array-based genome-wide chromosomal imbalance and DNA methylation analysis. We observed a wide spectrum of evolutionary patterns ranging from almost no evolution to divergent evolution within recurrent non-transformed t(14;18) FL. Remarkably, we observed a correlation of the magnitude of evolutionary divergence across all genetic and epigenetic levels suggesting co-evolution. The distribution of coding mutations in driver genes and the correlation with SHM suggest CREBBP and AID to be potential modifiers of genetic and epigenetic co-evolution in FL.

Genome-wide analysis of pediatric-type follicular lymphoma reveals low genetic complexity and recurrent alterations of TNFRSF14 gene

“…Conventional cytogenetics was available in 3 cases; 2 of them (PTFL25, PTFL36) presented a normal karyotype 46,XY in all cells studied whereas case PTFL24 displayed a 47,XY,add(7)(q36),18 [15]/ 46,XY [5] altered karyotype (supplemental Figure 1A).…”

“…10,11 In past years, the genetic landscape of conventional FL, beyond the well-known BCL2 translocation, 12 has been characterized comprehensively using next-generation sequencing (NGS). [13][14][15][16][17][18] This and similar high-throughput approaches revealed that germinal center (GC)-derived lymphomas are characterized by frequent mutations of histonemodifying genes. In adult-type FL, histone methyltransferase KMT2D (formerly MLL2) and EZH2, and the histone acetylases CREBBP, EP300, and MEF2B, are the most commonly mutated genes.…”

“…19 This suggests that progression from t (14;18) 1 premalignant precursor cells to FL is likely the result of epigenetic alterations. 14,15 PTFL is also a lymphoma derived from GC cells, but without the characteristic t(14;18) translocation. However, mutational analyses of histone-modifying genes, important for the pathogenesis of FL, have not been performed so far in PTFL.…”

DC-SIGN–expressing macrophages trigger activation of mannosylated IgM B-cell receptor in follicular lymphoma

“…In addition, whereas FL cells carry evidence of intraclonal evolution related to the ongoing somatic hypermutation process, mutational analysis of immunoglobulin variable regions reveals a counterselection of mutations affecting BCR structural integrity. 3,4 Finally, resistance to anti-idiotype therapy was shown to rely on mutations of the targeted immunoglobulin sequence rather than on loss of BCR expression. 5,6 Study of the FL BCR signaling profile highlighted a lack of constitutive activation together with a strong interindividual variability in both magnitude and kinetic of the signal.…”

Epigenetic Dysregulation in Follicular Lymphoma

“…Despite this, hypermethylation of tumor suppressor genes has been demonstrated in numerous studies including FL [56,57], with a significant overlap noted between hypermethylated CpGs and PRC2 target genes in embryonic stem cells [58]. Although initial reports suggested conservation of methylation profiles between paired pre-and post-transformation samples [58], the introduction of higher resolution platforms, suggests measurable differences in relapsed and more aggressive tumors [59,60]. Recent studies by Clozel et al propose a paradigm shifting change in how epigenetic therapies may be used to greatest effect; in a study of DLBCL, low-dose DNMTi exposure was used as a means of sensitizing chemoresistant tumors to doxorubicin through increased expression of a restricted number of genes including SMAD1 and demonstrated that combination of pretreatment with 5-azacitidine followed by chemoimmunotherapy recapitulated this observation in a Phase I clinical trial [61].…”