Somatic mutations of the translocated bcl-2 gene are associated with morphologic transformation of follicular lymphoma to diffuse large-cell lymphoma.
BACKGROUND
Ninety percent of low-grade follicular lymphomas (FLs) carry the t(14;18) translocation. This event juxtaposes the bcl-2 oncogene to the immunoglobulin (Ig) heavy-chain gene and leads to bcl-2 gene overexpression. Morphologic transformation of FL to high-grade lymphoma is associated with multiple secondary chromosomal abnormalities of the neoplastic cells.


METHODS
To analyze whether additional structural alterations of the translocated bcl-2 gene are associated with morphologic transformation of FL, we PCR-amplified, cloned, and sequenced the major breakpoint region (MBR) and the open reading frames (ORF) of the translocated bcl-2 oncogene in six paired samples of FL and subsequent diffuse large-cell lymphoma (DLL).


RESULTS
In five cases, FL and DLL cells were clonally related, as suggested by the identical MBR sequences, but in one case they were different. PCR single-strand conformation polymorphism (SSCP) and sequence analyses were performed for identification of structural alterations of the bcl-2 gene in the OFR region corresponding to the 239 amino acid p26-bcl-2a protein. In three of the six patients, a total of 11 point mutations of the ORF were detected in the DLL cells. Four of them, at positions 29, 46, 59, and 106, yielded amino acid replacements.


CONCLUSIONS
These findings demonstrate that FL and DLL cells may be clonally related or unrelated. They also show that transformation of FL cells can be associated with somatic point mutations of the bcl-2 oncogene ORF sequence resulting in alteration of the p26-bcl-2a gene product.
Matolcsy
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A
Department of Pathology, University Medical School of Pécs, Hungary.
Warnke
R A
RA
Knowles
D M
DM
D001483:Base Sequence; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D019254:Genes, bcl-2; D006801:Humans; D008224:Lymphoma, Follicular / Q000235:genetics* / Q000473:pathology; D016403:Lymphoma, Large B-Cell, Diffuse / Q000235:genetics* / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation; D014178:Translocation, Genetic