Genome-wide copy-number analyses reveal genomic abnormalities involved in transformation of follicular lymphoma

Abstract

• Chromosome copy-number alterations that may affect immune surveillance and the NF-kB and p53 pathways are more frequent in tFL than FL.• Abnormalities involving chromosomes 6 and X are predictive of overall survival in FL.Follicular lymphoma (FL), the second most common type of non-Hodgkin lymphoma in the western world, is characterized by the t(14;18) translocation, which is present in up to 90% of cases. We studied 277 lymphoma samples (198 FL and 79 transformed FL [tFL]) using a single-nucleotide polymorphism array to identify the secondary chromosomal abnormalities that drive the development of FL and its transformation to diffuse large B-cell lymphoma. Common recurrent chromosomal abnormalities in FL included gains of 2, 5, 7, 6p, 8, 12, 17q, 18, 21, and X and losses on 6q and 17p. We also observed many frequent small abnormalities, including losses of 1p36.33-p36.31, 6q23.3-q24.1, and 10q23.1-q25.1 and gains of 2p16.1-p15, 8q24.13-q24.3, and 12q12-q13.13, and identified candidate genes that may be driving this selection. Recurrent abnormalities more frequent in tFL samples included gains of 3q27.3-q28 and chromosome 11 and losses of 9p21.3 and 15q. Four abnormalities, gain of X or Xp and losses of 6q23.2-24.1 or 6q13-15, predicted overall survival. Abnormalities associated with transformation of the disease likely impair immune surveillance, activate the nuclear factor-kB pathway, and deregulate p53 and B-cell transcription

Cell of origin of transformed follicular lymphoma

“…Historically, TFL was considered to be related to the GCB subtype of de novo DLBCL, based on its transcriptional profile and the landscape of genetic alterations. 13,23 In keeping with the report by Bouska et al, 26 our study shows that a majority (80%) of TFL cases are of the GCB phenotype, but that a significant minority (16%) can nonetheless be identified as being of the ABC phenotype using the Lymph2Cx assay. In our series, ABC TFL cases did not have a poorer outcome after transformation than GCB TFL cases, although a definitive conclusion cannot be drawn due to the relatively small number of ABC cases and treatment heterogeneity.…”

“…23 In the study reported by Bouska et al, 42 out of 59 (71%) TFL cases were reported to be of the GCB phenotype and 17 out of 59 cases (29%) of a non-GCB phenotype. 26 In addition, whereas assessment of translocations involving both the MYC and either the BCL2 or BCL6 genes ("double-hit lymphoma") allows for identification of a poor-risk category of de novo GCB-type DLBCL, [27][28][29] similar prognostic implications are less well studied in TFL. In this study, we sought to assess whether transformation can be predicted at the time of FL diagnosis using clinical annotation and information on histologic grade, fluorescence in situ hybridization (FISH) break-apart assays for recurrently rearranged genes (BCL2 and BCL6), and IHC for CD10, BCL6, and IRF4.…”

Whole-genome integrative analysis reveals expression signatures predicting transformation in follicular lymphoma

“…Gain of X is associated with inferior outcome in FL. [1][2][3][4] Analysis of 131 FL-samples in the LLMPP data set 10,17 confirmed these results (supplemental Figures 2-5). Using Ingenuity Systems Pathway Analysis, the molecular network most enriched for cis-genes was identified ( Figure 1C).…”

“…Most cases of transformed FL are classified as GCB subtype of DLBCL by gene expression profile or immunophenotype. 18 Using a high-resolution SNP array, copy number profiles of FL, and transformed FL showed similarities with the GCB, as well as the ABC subtype of DLBCL, 3,19 and genes involved in NFkB signaling were targeted by recurrent copy number aberrations. The predictive power of 6 NFkB target gene scores suggests that attainment of a more ABC-like phenotype predisposes FL for transformation.…”

“…[1][2][3][4] Most alterations span large genomic regions involving hundreds of genes, thus offering limited cues for identification of genes driving the development of FL. Elevated expression of c-MYC and other genes promoting proliferation, inactivation of TP53 and CDKN2A, dysregulation of p38-mitogen-activated protein kinase (MAPK), and mutations of BCL6 have been implicated in subsets of cases with transformation.…”