2
Basic Cytogenetics and the Role of Genetics in Cancer Development
A
B
Fig. 2.11
(A)
Karyotype of a diffuse large B-cell lymphoma
exhibiting a characteristic t(3;14)(q27;q32) chromosomal translocation (arrows). Other
abnormalities such as additional material of unknown origin attached to the 1
p36 chromosomal region of one chromosome 1, to the 6p24p25 chromosomal
regions of both chromosomes 6, and deletion of the 7p21 segment of one chromosome 7 are additional aberrations reflecting clonal evolution. (B)
Metaphase
FISH
with the use of a dual-color (green and red) break-apart probe specific to the
BCL6
gene. The yellow signal (juxtaposition of green and red colors)
identifies the normal
BCL6
gene, whereas splitting of the green and red signals indicates a disruption of the other
BCL6
gene subsequent to the t(3;14)
chromosomal translocation.
mapping to the 7q31 chromosomal region were consistently
downregulated, among which three were found to be very
SMZL-specific:
ILF1, Senataxin,
and
CD40.30
Nodal marginal zone lymphoma (NMZL) is a very rare dis-
ease. However, local regional lymph node of MALT lymphoma
is virtually indistinguishable from NMZL, requiring clinical
information and, in some respect, cytogenetic data to diagnose
it. NMZL is characterized by frequent trisomies of chromosomes
3, 7, and 18, but the characteristic translocations of MALT
lymphoma are never seen.12
Small Lymphocytic Lymphoma
The histology, immunophenotypic and cytogenetic features of
small lymphocytic lymphoma are indistinguishable from the
more common CLL.12 Chromosomal aberrations observed in
SLL include thus trisomy 12, 11q, and 17p deletions—all of
them being poor-risk cytogenetic parameters—and a 13q14
deletion which is considered as a marker of good prognosis. A
t(14;19)(q32;q13) translocation occurs infrequently in SLL and
juxtaposes the
BCL3
gene located on chromosome 19 next to
the enhancer region of the
Ig-heavy-chain
gene, leading to BCL3
overexpression. When present, it confers a more aggressive
behavior.31
Lymphoplasmacytic Lymphoma
Lymphoplasmacytic lymphoma (LPL) is a rather uncommon
entity but its diagnosis remains challenging for most patholo-
gists. Cytogenetic investigations had previously considered the
t(9;14)(p13;q32)—juxtaposing the
PAX5
transcription factor
with the
Ig-heavy-chain
gene enhancer—as characteristic of LPL,
but more recent studies question the accuracy of this associa-
tion. Firstly, no
PAX5
rearrangement was detected in a series of
13 LPL.32 Secondly,
PAX5/IgH
rearrangement was observed in
other types of lymphoma including T-cell-rich B-cell lymphoma,
post-transplantation diffuse large B-cell lymphoma, and some
cases of SMZL.33
Diffuse Large B-cell Lymphoma
Diffuse large B-cell lymphoma is a very heterogeneous clin-
icopathologic entity, displaying numerous and disparate chro-
mosomal aberrations. In this section, we will only focus on
the most frequent cytogenetic aberrations observed in DLBCL,
hence chromosomal translocations involving
BCL6, BCL2
and
C-MYC
oncogenes.
The translocations involving the 3q27 chromosomal region
are the most characteristic and frequent cytogenetic aberrations,
detected in 30 to 40% of DLBCL12 (Figs 2.11A and 2.11B). The
3q27 breakpoint involves the
BCL6
gene, which is required
for germinal center (GC) formation and the B-cell immune
response. The gene partners of the
BCL6
chromosomal trans-
locations are multiple. They most often involve the
Ig-heavy-
or
-light-chain
(k and A
.) genes on chromosome bands 14q32, 2p11
and 22q11, but more than 20 non-
Ig
partners have also been
described, a phenomenon termed "promiscuous transloca-
tion".34 Whatever the partner is, the chromosomal translocation
brings the entire coding sequence of
BCL6
under the control of
a replaced promoter that will cause its deregulated expression
during B-cell differentiation.
BCL6
plays a key role in the generation of a germinal center
by B cells. It encodes a transcriptional repressor protein that
downregulates the expression of the B-lymphocyte-induced
maturation protein 1 (
BLIMP1
) gene necessary for plasma cell
differentiation, and also the expression of p27kip1, cyclin D2,
and P53 which control the cell cycle, apoptosis, DNA repair, and
maintenance of genomic stability.35 In a normal situation,
BCL6
expression is tightly regulated during B-cell ontogenesis, being
33
previous page 39 ComprehensiveCytopathology 1104p 2008 read online next page 41 ComprehensiveCytopathology 1104p 2008 read online Home Toggle text on/off