title: Transformation of follicular lymphoma to diffuse large cell lymphoma is associated with a heterogeneous set of DNA copy number and gene expression alterations.
abstract: Genomic aberrations in a series of paired biopsy samples from patients who presented initially with follicle center lymphoma (FCL) and subsequently transformed to diffuse large B-cell lymphoma (DLBCL) were measured by array comparative genomic hybridization (CGH). The consequences of these aberrations on gene expression were determined by comparison with expression analysis on these specimens using cDNA microarrays. A heterogeneous pattern of acquired genomic abnormalities was observed upon transformation, some of which were recurrent in small subsets of patients. Some of the genomic aberration acquired upon transformation, such as gain/amplification of 1q21-q24, 2p16 (REL/BCL11A gene loci), 3q27-q29 (including the BCL6 locus), 7q11.2-q22.1, 12pter-q12, 18q21 (including the BCL2 locus) and Xq, and deletion of 6q22-q24, 13q14-q21 and 17p13 (P53 locus) have been previously implicated in the FCL/DLBCL pathogenesis. In addition, novel genomic imbalances not previously reported in association with FCL transformation, such as overrepresentation of 4p12-pter, 5p12-p15, 6p12.3-p21, 9p23, 9q13-q31, 16q, 17q21, and loss of 1p36.3, 4q21-q23, 5q21-q23, 9q31-qter, 11q24-q25, and 15q23, were identified. We observed a differential expression profile of many genes within regions of gain and deletion upon transformation, including novel target genes associated with FCL transformation. However, other genes did not show deregulated expression despite their location within these areas. In summary, the combination of array CGH and expression analysis provides a more comprehensive picture of the transformation of FCL to DLBCL. This process is associated with the acquisition of a variable spectrum of genomic imbalances affecting recurrent chromosomal areas that harbor overexpressed or underexpressed genes targeted upon transformation.
authors.affiliation: Department of Hematology and Medical Oncology, Hospital Clinico, University of Valencia, Spain. martinez_jos@gva.es
authors.forename: Jose A
authors.initials: JA
authors.lastname: Martinez-Climent
authors.forename: Ash A
authors.initials: AA
authors.lastname: Alizadeh
authors.forename: Richard
authors.initials: R
authors.lastname: Segraves
authors.forename: David
authors.initials: D
authors.lastname: Blesa
authors.forename: Fanny
authors.initials: F
authors.lastname: Rubio-Moscardo
authors.forename: Donna G
authors.initials: DG
authors.lastname: Albertson
authors.forename: Javier
authors.initials: J
authors.lastname: Garcia-Conde
authors.forename: Martin J S
authors.initials: MJ
authors.lastname: Dyer
authors.forename: Ronald
authors.initials: R
authors.lastname: Levy
authors.forename: Daniel
authors.initials: D
authors.lastname: Pinkel
authors.forename: Izidore S
authors.initials: IS
authors.lastname: Lossos
mesh_terms: D022981:Allelic Imbalance; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002869:Chromosome Aberrations; D002872:Chromosome Deletion; D002877:Chromosomes, Human / Q000235:genetics / Q000648:ultrastructure; D018076:DNA, Complementary / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics*; D018450:Disease Progression; D005784:Gene Amplification; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D020411:Oligonucleotide Array Sequence Analysis
chemical_list: D018076:DNA, Complementary; D004273:DNA, Neoplasm