CHAPTER X CHAPTER 4 - Cancer et environnement

crucial for the development of this cancer,
in particular related to invasive
growth {2236}.
Several candidate genes have been proposed
to explain the gain of 12p in
TGCTs. These included KRAS2, which is
rarely mutated and sometimes overexpressed
in TGCTs {1818,1829,1953,
2192,2436}, and cyclin D2 (CCND2)
{1128,2325,2404,2436}. The latter might
be involved via a deregulated G1-S
checkpoint. A more focused approach
to the identification of candidate genes
was initiated by the finding of a metastatic
seminoma with a high level of amplification
of a restricted region of 12p, cytogenetically
identified as 12p11.2-p12.1
{2530}. Subsequently, primary TGCTs
have been found with such an amplification
{1360,1793,1795,2147,2221,2914}.
The 12p-amplicon occurs in about 8-
10% of primary seminomas, particularly
in those lacking an i(12p) {2914}, and it
is much rarer in non-seminomas. This
suggests the existence of two pathways
leading to overrepresentation of certain
genes on 12p, either via isochromosome
formation, or an alternative mechanism,
possibly followed by high level amplification.
The seminomas with amplification
have a reduced sensitivity to apoptosis
for which DAD-R is a promising
candidate {2914}. Probably more genes
on 12p, in particular in the amplicon,
help the tumour cells to overcome apoptosis
{807}.
Molecular genetic alterations
Multiple studies on the possible role of
inactivation of tumour suppressor genes
and activation of proto-oncogenes in the
development of TGCTs have been
reported. Interpretation of the findings
must be done with caution if the data
derived from the tumours are compared
to normal testicular parenchyma, which
does not contain the normal counterpart
of the cell of origin of this cancer.
A significant difference in genome methylation
has been reported between seminomas
(hypomethylated) and non-seminomas
(hypermethylated) {882,2443}.
This could reflect simply their embryonic
origin, and the capacity of the non-seminomas
to mimic embryonal and extra
embryonal development. This is for
example supported by their pattern of
expression of OCT3/4, also known as
POU5F1 {2003} X-inactivation {1538}, as
well as their telomerase activity.
Fig. 4.05 Comparative genomic hybridization on isolated intratubular germ cell neoplasia unclassified (left) and
three different histological variants of an invasive primary non-seminoma of the adult testis (left is embryonal
carcinoma, middle is teratoma, and right is yolk sac tumour). Note the absence of gain of 12p in the precursor
lesion, while it is present in the various types of invasive elements.
A
Fig. 4.06 Germ cell tumours genetics. A Representative comparative genomic hybridization results on chromosome
12 of a seminoma with an i(12p) (left panel), and gain of the short arm of chromosome 12, and additionally
a restricted high level amplification. B G-banding (left) and fluorescent in situ hybridization with a 12pspecific
probe stained in green on a metaphase spread of a primary testicular seminoma with a restricted 12p
amplification (chromosomes are counterstained in red) (right). Note the presence of a normal chromosome
12 (indicated by an arrow) and a chromosome 12 with a high level amplification (indicated by an arrowhead).
A
Fig. 4.07 Germ cell tumours genetics. Chromosomal expressed sequence hybridization (CESH) on A a seminoma
with an isochromosome 12p, and B a seminoma with a restricted 12p amplification. Note the predominant
expression of genes mapped within the 12p11.2-p12.2 region in both the seminoma with and without
the restricted amplification. These data indicate that genes from this region are involved in the development
of this cancer, even without the presence of a restricted amplification.
B
B
Several studies have been done to identify
genomic deletions, in particular by
means of detection of loss of heterozygosity
(LOH), with the goal to identify
candidate tumour suppressor gene-loci.
However, because of the aneuploid DNA
content of TGCTs, as well as their embryonic
nature, these data have to be
interpreted with caution {1536}. In fact,
aneuploid cells are thought to predominantly
loose genomic sequences, resulting
in LOH, expected to affect about
200.000 regions, which might not be
involved in initiation of the malignant
226 Tumours of the testis and paratesticular tissue