2
Basic Cytogenetics and the Role of Genetics in Cancer Development
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Fig. 2.9 Karyotype of mantle cell lymphoma
displaying the t(11;14)(q13;q11) chromosomal
translocation (arrows), associated with multiple
additional abnormalities such as interstitial
deletion involving one chromosome 13, loss
of the normal chromosome 14, and marker
chromosome (A). This profile is observed in
aggressive cases.
part of the
IgH
locus on chromosome 14q32 to the entire coding
sequence of
BCL1
oncogene, also named
Cyclin D1
or
PRAD1,
located on chromosome 11q13.23
BCL1
gene is thus brought
under the control of an
IgH
enhancer, leading to overproduction
of cyclin D1 protein, a mechanism similar to that observed for the
BCL2
oncogene in FL. Cyclin D1 is one of the key regulators of
the cell cycle, and complexes with CDK-4 and -6 in order to pro-
mote the G1/S-phase transition of the cell cycle. Increased Cyclin
D1 production in MCL will dramatically induce cells to enter the
S-phase and, therefore, tumor cell proliferation, by inhibiting the
cell cycle inhibitory effects of the retinoblastoma (Rb) and CDK
inhibitors p27kip1 proteins.24 Concurrent disruptions of other
cell cycle-associated genes contribute also to the pathogenesis of
MCL. In particular, homozygous deletions of the CDK inhibitor
p16INK4 were observed in aggressive variants of MCL. p16INK4 is
an inhibitor of CDK-4 and -6 and thus maintains the Rb protein
activity by preventing its phosphorylation. p16INK4 deletion and
an increased level of Cyclin D1 may therefore work together in
promoting the G1/S-phase transition in MCL cells.
The t(11;14) translocation is very specific to MCL among
other B-NHL and is detected by conventional cytogenetics in
60-75% of MCL cases, but this number rises to nearly 100%
with the use of FISH.
Beside the presence of t(11;14) translocation, the study of the
overall cytogenetic profile brings prognostic meanings. Normal
karyotype or karyotype with a single t(11;14) is associated with
the typical form of MCL and is a good prognostic factor. In the
majority of aggressive cases, t(11;14) is associated with a complex
karyotype including numerous structural and numerical altera-
tions of chromosomes 1, 2, 3, 9, 11, 13, 17 as well as unidenti-
fied chromosomal aberrations (markers).25 Also, near-tetraploid
karyotypes (hence ±92 chromosomes) seem to be characteristic
for the blastoid variant MCL. These karyotypic features occur-
ring in aggressive MCL cases reflect the existence of alterations
in both the DNA damage response pathways and mitotic check-
points that may constitute another important pathogenetic
mechanism in this lymphoma subtype. Indeed, one of the most
frequently additional cytogenetic aberrations observed in MCL
is deletion in the 11q22-23 chromosomal region where the
ATM
(ataxia-telangiectasia mutated) gene is located.
ATM
gene plays
a key role in genomic stability by activating gatekeeper and care-
taker genes such as
p53
and
BCRA1
in response to DNA dam-
age.26 ATM inactivation in MCL is associated with a high number
of chromosomal alterations, suggesting that it may, at least in
part, be responsible for the chromosomal instability in these
lymphomas.26
Marginal Zone B-cell Lymphoma
Several chromosomal abnormalities are encountered in mar-
ginal zone B-cell lymphomas (MZL) and are distributed accord-
ing to the three different subtypes: extranodal MZL of MALT
type, nodal MZL, and splenic MZL.
In MALT lymphoma, four main recurrent chromosomal
translocations have been observed and demonstrate a site-spe-
cificity in terms of their incidence: t(11;18)(q21;q21), t(1;14)
(p22;q32), t(14;18)(q32;q21), and the recently described t(3;14)
(p14.1;q32) (Table 2.1). The latter, limited to MALT lymphoma
of the thyroid, skin and ocular adnexa regions, leads to the jux-
taposition of the transcription factor Forkhead box-P1
(FOXP1)
next to the enhancer region of the
IgH
gene.27 This molecular
event results in
FOXP1
gene overexpression but the patho-
genetic relevance of this translocation is still not known.
The three other translocations affect a common signaling
pathway, resulting in the constitutive activation of the nuclear
factor-KB (NF-kB), a transcription factor which plays a major
role in cellular activation, proliferation and survival.28 The
t(1;14)(p22;q32) is detected in approximately 5% of MALT lym-
phoma, arising in localizations such as stomach, intestine, and
lung. This translocation results in overexpression of the
BCL10
gene (chromosome 1p22) due to its juxtaposition with the
IgH
gene enhancer. The t(14;18)(q32;q21) translocation, cytoge-
netically identical to the t(14;18)(q32;q21) involving
BCL2
gene in follicular lymphoma, is observed in more or less 20%
of MALT lymphoma, especially in non-gastrointestinal localiza-
tions such as liver, lung, salivary glands, skin, and ocular adnexa.
This translocation brings the mucosae-associated lymphoid tis-
sue
(MALT1)
gene, also involved in antigen-receptor-mediated
NF-kB activation, under the control of the
IgH
enhancer region,
with subsequent
MALT1
overexpression. The t(11;18)(q21;q21)
represents the most common translocation, accounting for
31
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