Transformation of follicular lymphoma to diffuse large B‐cell lymphoma proceeds by distinct oncogenic mechanisms

Abstract

Summary This study was undertaken to further elucidate the biological mechanisms underlying the frequent event of transformation of follicular lymphoma (FL) to diffuse large B‐cell lymphoma (t‐FL). The gene expression profiles of 20 paired lymph node biopsies, derived from the same patient pre‐ and post‐transformation, were analysed using the Lymphochip cDNA microarray. TP53 mutation analysis was performed and copy number alterations at the c‐REL and CDNK2A examined. Immunohistochemistry was performed on an independent panel of paired transformation paraffin‐embedded samples. Transformed follicular lymphoma was predominantly of the germinal centre B‐like phenotype both at the mRNA and protein level. Despite this homogeneity, transformation proceeded by at least two pathways. One mechanism was characterised by high proliferation, as assessed by the co‐ordinately expressed genes of the proliferation signature. This group was associated with the presence of recurrent oncogenic abnormalities. In the remaining cases, proliferation was not increased and transformation proceeded by alternative routes as yet undetermined. Genes involved in cellular proliferation prevailed amongst those that were significantly increased upon transformation and T cell and follicular dendritic‐associated genes predominated amongst those that decreased. t‐FL is a germinal centre B (GCB)‐like malignancy that evolves by two pathways, one that is similar in proliferation rate to the antecedent FL and the other that has a higher proliferation rate and is characterised by the presence of recognised oncogenic abnormalities.

Genome-wide profiling of follicular lymphoma by array comparative genomic hybridization reveals prognostically significant DNA copy number imbalances

“…It suggests that deletion of 1p36 may predispose patients to subsequent transformations with high proliferation rate, as described by Davies et al and Lossos et al, rather than lower proliferative transformations. 41,42 Deletion of 6q is detected frequently in acute lymphoblastic leukemia, chronic lymphocytic leukemia, multiple myeloma, DL-BCL, and FL. 32,43 Different studies have shown various regions to be involved; however, only 1 of these has focused specifically on FL in which a 2.3-Mb region of deletion was identified at 6q16.3 in approximately 15% FL cases.…”

Translocations involving 8q24 in Burkitt lymphoma and other malignant lymphomas: a historical review of cytogenetics in the light of todays knowledge

“…Apart from the DLBCL cases, these cases are commonly thought to represent transformed disease and therefore may harbor a non-IG-MYC breakpoint or additional translocations (for example, involving BCL2 or CCND1), as well as a higher number of numerical aberrations. [47][48][49][50] Indeed, the complexity score was much higher in the other B-NHL cases (Figure 4a; significance of difference Po0.0001) and gains of 7, 11p, 11q11-22, 12, 18 and X and loss of 4q, 6q13-27, 9, 10p, 15, 17p13 and 17q11-23 were more common compared with the BL core subset ( Figure 5). In addition, patients were older (mean 50 versus 23.5 years, Po0.0001; Figure 2), and the male/female ratio was lower (Supplementary Table 3).…”

Different Histopathological Types of Orbital Lymphoma 16 Years after Systemic Follicular Lymphoma: Immunohistochemical and Immunogenetic Analyses of Two Cases

“…5 In recent studies, genomic changes have been revealed to occur during the transformation from follicular lymphoma to diffuse large B-cell lymphoma. 18,19 In Patient #2, additional nucleotide changes could have developed in the immunoglobulin heavy chain gene of lymphoma cells of the same clonal origin in the 16-year process of the transformation from follicular lymphoma to diffuse large Bcell lymphoma. 5 The goal of this study is to document the fact that orbital lymphomas occur as a recurrence of systemic lymphomas which have initially developed 16 years previously.…”