Genetics of Follicular Lymphoma Transformation

Abstract

Summary Follicular lymphoma (FL) is an indolent disease, but 30-40% of cases undergo histologic transformation to an aggressive malignancy, typically represented by diffuse large B cell lymphoma (DLBCL). The pathogenesis of this process remains largely unknown. Using whole-exome sequencing and copy-number analysis, here we show that the dominant clone of FL and transformed FL (tFL) arise by divergent evolution from a common mutated precursor through the acquisition of distinct genetic events. Mutations in epigenetic modifiers and anti-apoptotic genes are introduced early in the common precursor, while tFL is specifically associated with alterations deregulating cell-cycle progression and DNA-damage responses (CDKN2A/B, MYC, TP53), as well as with aberrant somatic hypermutation. The genomic profile of tFL shares similarities with that of germinal center B-cell-type de novo DLBCL, but also displays unique combinations of altered genes, with diagnostic and therapeutic implications.

Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation

“…Of these, CREBBP mutations were most stable throughout the course of disease, and the most significantly enriched mutations within ancestral EIPs. This is in line with prior observations that these mutations are also shared between the indolent and transformed phases of FL (13,14). In contrast, mutations within KMT2D had variable patterns of representation within diagnosis/relapse tumors from the same patient, and a lower frequency of events within EIPs across patients.…”

“…This and other evidence therefore suggests that BCL2 translocations are not sufficient for lymphomagenesis and may be harbored in FL precursors, and that secondary genetic alterations are needed to drive clinical disease (4, 9, 10). Next-generation sequencing studies of FL have identified frequent mutation of chromatin-modifying genes (CMGs) (11)(12)(13)(14)(15). These include inactivating mutations of genes that apply activating euchromatin-associated marks [lysine-specific methyltransferase 2D (KTM2D), CREB binding protein (CREBBP), and E1A binding protein p300 (EP300)] and activating mutations within a gene that applies a repressive heterochromatin-associated mark (enhancer of zeste homolog 2, EZH2).…”

Large-scale microarray profiling reveals four stages of immune escape in non-Hodgkin lymphomas

“…In B-NHL, genetic and epigenetic alterations create tumor phenotypes that are protected against immune cytolysis. [1][2][3][4][5][6][7] Immune escape also evolves through the concerted upregulation of gene expression. 8 For example, the B-NHL subtypes FL and DLBCL upregulate the expression of genes involved in the PD1/PDL1-2 axis, the CTLA4 ligand axis, the biosynthesis of immunosuppressive Galectin 3, and the genes IDO1, VEGFA, PGE2, IL10, and HGF, among several others.…”

Dual HDAC and PI3K Inhibitor CUDC-907 Downregulates MYC and Suppresses Growth of MYC-dependent Cancers

“…Activating genetic alterations of MYC, including genomic rearrangements, copy number gains, or amplifications, are common driving events in certain cancers. For example, acquisition of MYC alterations and subsequent upregulation of MYC and MYC target genes have been implicated as key events in the transformation of indolent follicular lymphoma (FL) to highly aggressive diffuse large B-cell lymphoma (DLBCL) and is also observed in de novo DLBCL (2,3). Alternatively, other oncogenic events drive cancer by inducing epigenetic changes that promote MYC overexpression such as in NUT midline carcinoma (NMC), a poorly differentiated, highly aggressive subtype of squamous cell carcinoma that primarily arises in midline organs (4).…”