Mutation analysis of the 5 ' noncoding regulatory region of the BCL-6 genein non-Hodgkin lymphoma: evidence for recurrent mutations and intraclonal heterogeneity
Is. Lossos et R. Levy, Mutation analysis of the 5 ' noncoding regulatory region of the BCL-6 genein non-Hodgkin lymphoma: evidence for recurrent mutations and intraclonal heterogeneity, BLOOD, 95(4), 2000, pp. 1400-1405
The BCL-6 proto-oncogene is involved in the genesis of non-Hodgkin lymphoma
(NHL), Rearrangements due to chromosomal translocations and somatic mutati
ons of the 5' noncoding regulatory region of the BCL-6 gene are potential m
echanisms for altering its expression in NHL, To further elucidate the natu
re of the somatic mutations in the regulatory region of this gene, we have
studied 10 healthy donors and 11 NHL biopsy samples by extensive molecular
cloning and sequencing, In addition, we analyzed the BCL-6 genes of tumor a
nd nontumor cells from 2 of the cases. The germ line sequence of this regio
n was defined, which differs in 7 positions from that previously reported.
In addition, 1 polymorphic Variation at position 397(G or C) was identified
. Deletions, insertions, and repeated substitution mutations were detected
among the molecular isolates in 8 tumor specimens, with a mutational incide
nce ranging from 1.3x10(-3) to 1.3 x 10(-2)/bp (base pair). A total of 20 d
istinct substitution mutations, 1 insertion and 3 deletions were observed.
One of these deletion mutations and 2 of the substitutions were observed in
more than 1 tumor specimen from different individuals. In 3 tumor samples,
identical mutations affecting both alleles were observed. These findings s
uggest the presence of mutational hot spots and hot specific events, a find
ing supported by our compilation of previously published data, In 6 samples
, the nucleotide sequences showed evidence of intraclonal heterogeneity, co
nsistent with a stepwise ongoing mutational process affecting the BCL-6 gen
e in the tumor cells. These mutations accumulating in the regulatory region
of the BCL-6 gene could play a role in lymphoma progression and in the tra
nsformation of follicular lymphomas to more aggressive large cell lymphomas
, (C) 2000 by The American Society of Hematology.