Higher grade transformation of follicular lymphoma: phenotypic tumor progression associated with diverse genetic lesions

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Abstract

Higher grade histological transformation of follicular lymphoma (FL) to more aggressive diffuse large B-cell lymphomas (DLBCL) occurs in 10–60% of the cases. Review of the current knowledge of genetic and molecular alterations associated with the higher grade transformation of FCL suggests that the process that leads to clinically and phenotypically similar end-point can occur by functionally diverse genetic lesions. The most commonly identified genetic alterations associated with the FCL transformation are TP53 gene mutations, inactivation of CDKN2A and CDKN2B genes and deregulation of the C-MYC gene. These lesions affect different aspects of normal cell physiology (apoptosis, cell cycle control, and proliferation) and are potential targets for gene-specific therapies.

Section snippets

TP53 gene

The TP53 gene, located on chromosome 17p13.1, encodes for a protein with 393 amino acids, which acts as a multifunctional transcription factor involved in cell cycle arrest, apoptosis, cell differentiation, replication, DNA repair, and maintenance of genomic stability [20], [21]. In response to DNA damage or other cellular stress, p53 protein levels and its activity as a transcriptional factor increase. The stabilization and activation of p53 result in the arrest of cell-cycle progression in

C-MYC gene

The C-MYC proto-oncogene encodes a transcription factor that plays a key role in cell proliferation, differentiation, metabolism, cell adhesion, and apoptosis [29], [30], [31], [32]. In normal cells, C-MYC expression is tightly regulated in response to growth signals. Non-proliferating or quiescent cells generally express no detectable C-MYC, but the gene is rapidly induced following mitogenic stimulation and continues to be expressed in proliferating cells. C-MYC is frequently deregulated in

CDKN2A and CDKN2B genes

CDKN2A and CDKN2B genes, mapped to chromosome 9p21, encode p16 and p15 proteins, respectively, that function as cyclin-dependent kinase (CDK) inhibitors. They exert a tumor-suppressive function by specifically interfering with the catalytic activity of complexes between cyclin D and CDK4 and CDK6 [54], [55]. By competing with cyclin D in binding to CDKs, p16 and p15 prevent activation of these kinases, leading to inhibition of the retinoblastoma protein (Rb) phosphorylation and thus preventing

BCL6 gene

The BCL6 is a proto-oncogene, identified by virtue of its involvement in recurrent chromosomal translocations affecting band 3q27. It encodes a POZ/Zinc finger sequence-specific transcriptional repressor, which is normally expressed in B cells and CD4+T cells within GC and controls GC formation as well as represses T helper cell type 2-mediated inflammatory responses [63], [64], [65], [66], [67]. Clonal BCL6 rearrangements cluster within a highly conserved 4.0 kb regulatory region spanning the

BCL-2 gene

The primary molecular abnormality associated with up to 90% of FL is the t(14;18)(q32;q21) chromosomal translocation that juxtaposes the BCL-2 proto-oncogene to the Ig heavy-chain joining region [86], [87]. In most cases, the breakpoints on chromosome 18 are clustered in the 3′end of the last BCL-2 exon or within the 3′ un-translated region of the gene, leaving its open reading frame (ORF) intact [88], [89]. This molecular event results in the deregulation of BCL-2 gene expression, leading to

RAS gene

RAS proteins are prototypical G-proteins that have been shown to play a key role in signal transduction, proliferation, and malignant transformation. The RAS gene family consists of three functional genes, H-RAS, N-RAS, and K-RAS, which encode 21 kD proteins, which are associated with the inner leaflet of the plasma membrane. Mutations of the RAS genes, most commonly affecting codons 12, 13, and 61, are frequent genetic aberrations found in 20–30% of all human tumors, although the incidence is

FAS gene

The FAS antigen (CD95/APO-1) is a 45 kD transmembrane protein receptor of the tumor necrosis superfamily which initiates apoptosis upon cross-linking to FAS ligand (FASL) [105], [106], [107]. In the B-cell lineage, FAS is specifically expressed at the germinal GC stage of differentiation and may contribute to the propensity of GC B cells to undergo apoptosis. FAS gene has been reported to undergo somatic mutations in normal GC lymphocytes [108], [109]. FAS is considered to be a tumor suppressor

ATM gene

The ATM gene product plays a central role in signaling DNA damage, predominantly double-strand breaks in DNA, and in activating checkpoints to slow the progress of cells carrying DNA damage through the cell cycle [119]. The ATM protein, like p53, can play a key role as a guardian of the genome and its inactivation may be implicated in the development of sporadic hematological malignancies. Indeed, ataxia–telengiectasia (A–T) patients, in whom the ATM gene function is lost, exhibit an extremely

Microsatellite instability (MSI)

MSI is defined as the presence of alterations in the germline size of microsatellite repeats and is a marker of reduced efficacy of cellular mismatch repair systems, It is most commonly caused by mutations in specific DNA repair genes. MSI represents one of the most common genetic lesions of human solid tumors, however, it is rare in NHL [137]. Nagy et al. [94] searched for acquisition of MSI during FL transformation. A high level (>40% positive markers) of MSI was associated with histological

Chromosomal changes associated with FL transformation

Chromosomal analysis is a classic powerful mean to resolve the biological complexity of tumors and to gain insights into their clinical behavior. However, the data on the chromosomal abnormalities in FL transformation is relatively scarce since (a) the cytogenetic analysis of lymphoid malignancies is difficult because of the low number of high-quality metaphase cells, and (b) the limited availability of paired pre- and post-transformation specimens suitable for genetic studies. Nevertheless,

Global changes in gene expression profiles

Most of the studies examining the molecular mechanisms of the higher grade transformation of FCL applied traditional research approaches in molecular biology that examined single genes that are likely to be involved in the process of transformation. However, recent developments in biomedical research, such as design of the oligonucleotide or cDNA microarrays, harbor great potential to address the fundamental problem of FL transformation and enable the definition of gene expression patterns in

Summary and perspective

Major effort has been expanded during the last decades to elucidate the molecular pathogenesis of FL transformation. Although the total number of evaluated cases is relatively small (Table 2, Table 3) due to the limited availability of paired pre- and post-transformation specimens, the current data suggest that the process that leads to clinically and phenotypically similar end-point can occur by functionally diverse genetic lesions. Therefore, the expectation that a single genetic defect could

Acknowledgments

Some of the data summarized in this paper is the result of collaborative work with researchers at the Stanford University; Hospital Clı́nico, University of Valencia, Spain; and University of California, San Francisco. Key individuals who contributed to these studies are Ash A. Alizadeh, Maximilian Diehn, Roger Warnke, Yvonne Thorstenson, Peter J. Oefner, Patrick O. Brown, David Botstein Jose, A. Martinez-Climent, and Daniel Pinkel. Supported by Grants CA33399 and CA34233 from the USPHS-NIH.

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