2
Basic Cytogenetics and the Role of Genetics in Cancer Development
Fig. 2.14 Karyotype of a synovial sarcoma
with the specific t(X;18)(p11;q11) chromosomal
translocation (arrows). Losses and gains of other
chromosomes represent additional secondary
changes.
fuse the DNA-binding domain of PAX3 or PAX7 to the transacti-
vation domain of FKHR.
PAX
genes activate myogenesis, and
fork
head in rhabdomyosarcoma (FKHR)
is though to have pro-apop-
totic activities. The resulting
PAX-FKHR
fusion gene is a highly
potent activator with a transcriptional activity 10 to 100 times
as high as that brought by wild-type
PAX
gene. This enhanced
transcriptional activity is further amplified by mechanisms of
PAX-FKHR
fusion genes amplification. As the DNA-binding of
FKHR is lost in the PAX-FKHR fusion, any DNA-binding specifi-
city of the fusion gene is directed by the PAX sequence, leading
to dysregulated expression of downstream target genes of PAX
genes. Consequently, PAX3/FKHR will be able, firstly, to inhibit
cellular apoptosis through a PAX3 target gene, the anti-apop-
totic protein BCL-XL and, secondly, to activate
c-MET, PDGFaR,
or
c-RET
oncogene, downstream targets of PAX3 involved in
migration and proliferation of myogenic precursors.
Other sarcoma-associated fusion genes have been shown to
get tumoral properties by activating growth factor receptors.
MET
oncogene has been recently shown to be a direct transcrip-
tional target of the
ASPL-TFE3
fusion gene. Induction of MET
by ASPL-TFE3 results in strong MET autophosphorylation and
activation of downstream signaling in the presence of hepato-
cyte growth factor.48
Another question that remains a matter of debate is
whether these chromosomal translocations are sufficient for
neoplastic transformation.14,43 Although expression of certain
gene fusions can induce sarcoma in primary mesenchymal
progenitor cells, secondary mutations are likely to be required
for full malignancy as observed in the context of hemato-
logical disorders. Loss of tumor suppression genes expression
(such as
P16
and
RB)
is observed in more than 50% of vari-
ous sarcoma. Activation of common growth-factor pathways
not directly due to chromosomal translocation is described
in sarcomas including the insulin-like growth factor 1 (IGF1)
pathway in alveolar RMS, the platelet-derived growth factor
receptor (PDGFR) in DSRCT, and the c-KIT receptor path-
way in Ewing's tumors. Parallel to the situation observed in
childhood leukemia,49 it is possible that some chromosomal
translocations associated with childhood tumors arise during
Table 2.3
Sarcomas with complex karyotypes
Type o f sarcoma
Fibrosarcoma (other than congenital)
Leiomyosarcoma
Malignant fibrous histiocytoma
Osteosarcoma
Chondrosarcoma (types other than extraskeletal myxoid)
Liposarcoma (types other than myxoid)
Embryonal rhabdomyosarcoma
Malignant peripheral nerve-sheath tumour
Angiosarcoma
Neuroblastoma®
’ N e u r o b la s t o m a is q u o t e d in t h is t a b le a s it b e lo n g s t o t h e 's m a ll r o u n d b lu e c e ll
t u m o u r s ' g r o u p .
fetal development, leading to a "pre-malignant state" preced-
ing the sarcomatous transformation induced by additional
genetic aberrations.
Sarcomas with Complex Karyotypes
This group of sarcoma does not exhibit any specific and recur-
rent chromosomal translocation but rather complex karyo-
types with multiple numerical and structural aberrations
characteristic of severe genetic and chromosomal instability43
(Table 2.3) (Fig. 2.15). The underlying genetic mechanisms
frequently include alterations in cell-cycle genes such as
P53,
INK4A,
and
RB1
as well as genes directly involved in DNA-
repair pathways. Oncogene amplifications occur in cytogeneti-
cally complex sarcoma.
MDM2
and
MYCN
gene amplifications
are well-known examples.
MDM2
amplification is observed
in liposarcoma (other than myxoid) and malignant fibrous
histiocytomas.
MDM2
is a p53 inhibitor and its amplification
37
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