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Prepublished online as a Blood First Edition Paper on October 24, 2002; DOI 10.1182/blood-2002-07-2119.
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Blood, 15 April 2003, Vol. 101, No. 8, pp. 3109-3117
NEOPLASIA
Transformation of follicular lymphoma to diffuse large cell
lymphoma is associated with a heterogeneous set of DNA copy number
and gene expression alterations
Jose A. Martinez-Climent,
Ash A. Alizadeh,
Richard Segraves,
David Blesa,
Fanny Rubio-Moscardo,
Donna G. Albertson,
Javier Garcia-Conde,
Martin J. S. Dyer,
Ronald Levy,
Daniel Pinkel, and
Izidore S. Lossos
From the Department of Hematology and Medical
Oncology, Hospital Clinico, University of Valencia, Spain;
the Departments of Biochemistry and Medicine, Stanford University
School of Medicine, Stanford, CA; Comprehensive Cancer Center, and
Cancer Research Institute, University of California, San Francisco, CA;
the Department of Haematology, University of Leicester, Leicester,
United Kingdom.
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.

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