PART ONE
General Cytology
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Fig. 2.15
Typical example of a
complex
karyotype
as observed in
embryonal
rhabdomyosarcoma
showing multiple
numerical and structural abnormalities. the latter
(isochromosome 17q and two chromosome
markers) are marked with arrows.
will lead to inability of p53 to induce apoptosis in cells with
DNA damage, which, in turn, will induce genomic instability.
MYCN
amplification (Fig. 2.16) is used as a genetic parameter
for better therapeutic stratification of patients suffering from
neuroblastoma, one of the most frequent malignant tumors in
childhood.50
MYCN
is a member of the MYC family of proto-
oncogenes which are transcription factors promoting cell pro-
liferation and inhibiting terminal differentiation. In view of its
function,
MYCN
is involved in the genesis of a wide range of
cancers including neuroblastoma, small cell lung carcinoma,
some cases of medullary thyroid carcinoma, retinoblastoma,
and breast cancers. A forced expression of
MYCN
in central
nervous system cells in mouse leads to the development of
a subgroup of neuroblastomas, indicating that it is sufficient
for malignant transformation. Additional information on
sarcomas is found in Chapter 18.
Thyroid Carcinomas
Among epithelial malignancies, two histological types of thy-
roid carcinoma, namely the papillary and follicular thyroid car-
cinoma, deserve to be mentioned as they exhibit specific genetic
aberrations that represent reliable diagnostic parameters.
Papillary Thyroid Carcinoma
Papillary thyroid carcinoma (PTC) is characterized by rearrange-
ments of the
RET
oncogene, a receptor tyrosine kinase (RTK)
gene located on chromosomal region 10q11.2. These activating
rearrangements, called
RET/PTC,
are caused by either paracen-
tric inversion of chromosome 10 or balanced translocations
involving chromosome 10 and various chromosome partners51
(Table 2.4). The molecular consequences are fusion of the tyro-
sine kinase domain of
RET
with the 5' part of the various gene
partners with subsequent release of the extracellular ligand-
binding and juxtamembrane domains of RET receptor. As the
juxtamembrane domain negatively regulates RET mitogenic sig-
naling, its deletion contributes to RET/PTC activation, which is
Fig. 2.16 Interphase FISH
demonstrating amplification of the
M YCN
oncogene (red signals) in a case of neuroblastoma. The two green spots
correspond to centromeric probes specific for the chromosome 2 and used
as control for diploid status assesment of the analyzed cell.
further enhanced by dimerization potential brought by the gene
partner.52 This leads to ligand-independent activation of the RET
kinase, signaling pathway stimulation and cell-cycle activation;
a well-known oncogenic process in tumoral cells harboring RTK
rearrangements. As part of its oncogenic effect,
RET/PTC
directly
modulates genes involved in inflammation/invasion of the cell
such as various cytokines (GM-CSF, M-CS, IL6, etc.), chemo-
kines (CCL2, CXCL12, etc.), and chemokine receptors (CXCR4).
The induction of an inflammatory-type reaction may explain the
chronic inflammatory reaction observed in this type of cancer.52
The prevalence of
RET/PTC
in papillary thyroid carcinoma
is highly variable (0-87% ), depending on age of patient,
38
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