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Frequent incidence of somatic mutations in translocated BCL2 oncogenes of
non-Hodgkin's lymphomas
S Tanaka, DC Louie, JA Kant and JC Reed
Department of Pathology & Laboratory Medicine, University of
Pennsylvania, Philadelphia 19104-6082.
The majority of non-Hodgkin's B-cell lymphomas contain a t(14;18)
translocation that places the bc12 gene into juxtaposition with the
transcriptically active Ig heavy-chain locus, thus deregulating the
expression of this proto-oncogene. The bc12 gene product is a membrane-
associated mitochondrial protein that regulates cell survival through
unknown mechanisms. Although overproduction of the normal protein appears
sufficient for conferring a selective growth or survival advantage to B
cells, point mutations that alter the coding region of translocated bc12
genes have been described previously by others in a lymphoma cell line.
However, it is not known whether somatic mutations that alter BCL2 proteins
occur in vivo or whether they result from chemotherapy or arise through
other mechanisms. For these reasons, we obtained DNA from the
t(14;18)-containing tumors of five patients who had not undergone treatment
for their disease, and used a polymerase chain reaction (PCR)-mismatch
technique for rapid identification of point mutations in a portion of the
bc12 open reading frame (ORF) corresponding to the first 131 aminoacids
(aa) of the 239 aa p26 BCL2 protein. DNAs from two t(14;18)-containing cell
lines were also analyzed. Point mutations in this region of the bc12 gene
ORF were detected in three of five patients' tumors and in both cell lines.
PCR- mismatch analysis of bc12 in cell lines and non-Hodgkin's lymphoma
cases that lacked the t(14;18) translocation was negative, thus
establishing the specificity of these results. DNA sequencing determined
that these mutations are predicted to produce aa substitutions in the BCL2
proteins of two of the primary tumors and one of the cell lines.
Interestingly, two of the patients contained an identical C----T transition
that resulted in a nonconservative aa substitution (proline----serine) at
position 59 of the BCL2 protein. Further analysis excluded the possibility
that these mutations represented hereditary polymorphisms or PCR artifacts.
A cluster of four point mutations within the translocation + bc12 allele of
one patient had hallmarks of the somatic hypermutation mechanism that is
associated with Ig genes and that contributes to antibody diversity.
Because of the region of the bcl2 gene analyzed in these t(14;18)
translocations is located nearly 300 kbp from the Ig heavy-chain locus, our
data suggest that the Ig gene somatic hypermutation mechanism can act over
extreme distances of DNA. It remains to be established whether these
somatic mutations that alter BCL2 proteins influence the pathobiology of
nonHodgkin's lymphomas.
Volume 79,
Issue 1,
pp. 229-237,
01/01/1992
Copyright © 1992 by The American Society of Hematology
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