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Blood, Vol. 96 No. 2 (July 15), 2000:
pp. 635-639
Higher-grade transformation of follicle center lymphoma is
associated with somatic mutation of the 5' noncoding regulatory
region of the BCL-6 gene
Izidore S. Lossos and
Ronald Levy
From the Division of Oncology, Department of Medicine, Stanford
University Medical Center, Stanford, CA.
Follicle center lymphoma (FCL) is an indolent low-grade B-cell
non-Hodgkin's lymphoma (NHL) that frequently transforms to aggressive
diffuse large B-cell lymphoma (DLBCL). Histologic transformation of FCL
is commonly associated with accumulation of secondary genetic alterations. The BCL-6 gene is altered by
chromosomal rearrangements and mutations clustering in its 5'
noncoding regulatory region in up to 70% of primary DLBCL, but in a
significantly smaller subset of FCL. Previous studies have shown that
both chromosomal rearrangements and mutations could deregulate
BCL-6 expression. To evaluate the association between
progressive accumulation of BCL-6 regulatory region mutations
and the histologic transformation of FCL, we analyzed by extensive
cloning and sequencing paired biopsy specimens obtained at the time of
FCL diagnosis and transformation (6 patients) or FCL relapse (3 patients). In an additional patient, biopsy specimens obtained at the
time of diagnosis, FCL relapse, and subsequent transformation to DLBCL
were evaluated. The presence of identical mutations in the paired
diagnosis and posttransformation DLBCL specimens confirmed the common
clonal origin of both the pretransformation and the posttransformation
lymphomas. No new mutations in the 5' noncoding regulatory region
of the BCL-6 gene were detected in any of the specimens
evaluated at the time of FCL relapse. In contrast, 5 of the 7 transformed specimens contained new mutations not found in the paired
original biopsy specimens obtained at the time of FCL diagnosis or
relapse. The number of these new mutations ranged from 1 to 6 per
specimen. Some of the new mutations tended to cluster in certain areas
of the 5' noncoding regulatory region of the BCL-6 gene.
Our results show that transformation of FCL to DLBCL is associated with
accumulation of new mutations in the 5' noncoding regulatory
region of the BCL-6 gene, that by deregulation of the
BCL-6 gene expression may play a role in lymphoma transformation.
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