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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1400-1405
Mutation analysis of the 5' noncoding regulatory region of
the BCL-6 gene in non-Hodgkin lymphoma: evidence for recurrent
mutations and intraclonal heterogeneity
Izidore S. Lossos and
Ronald Levy
From the Division of Oncology, Department of Medicine, Stanford
University Medical Center, Stanford, CA.
The BCL-6 proto-oncogene is involved in the genesis of non-Hodgkin
lymphoma (NHL). Rearrangements due to chromosomal translocations and
somatic mutations of the 5' noncoding regulatory region of the
BCL-6 gene are potential mechanisms for altering its expression in NHL.
To further elucidate the nature 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 and nontumor cells from
2 of the cases. The germ line sequence of this region 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 incidence ranging from 1.3 × 10 3 to
1.3 × 102/bp (base pair). A total of 20 distinct
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 suggest the presence of mutational hot spots and hot specific events, a finding supported by our compilation of previously published data. In 6 samples, the nucleotide sequences showed evidence
of intraclonal heterogeneity, consistent with a stepwise ongoing
mutational process affecting the BCL-6 gene 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 transformation of
follicular lymphomas to more aggressive large cell lymphomas.
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