CHAPTER X CHAPTER 4 - Cancer et environnement

process at all {1524}. In addition, pluripotent
embryonic stem cells show a different
mutation frequency and type compared
to somatic cells {397}. In fact,
embryonic cells show a higher tendency
to chromosome loss and reduplication,
leading to uniparental disomies, which
are detected as LOH.
So far, the majority of LOH studies
focused on parts of chromosomes 1, 3,
5, 11, 12 and 18 {162,672,1384,1536,
1560,1645,1853,1855,1856,2045}.
Recurrent losses have been identified on
1p13, p22, p31.3-p32, 1q32, 3p, 5p15.1-
p15.2, q11, q14, q21, and q34-qter,
12q13 and q22, and 18q. No candidate
gene has yet been identified at 12q22
{162} in spite of the identification of a
homozygous deletion. Some of the candidate
tumour suppressor genes
mapped in the deleted genomic regions
in TGCTs have been investigated; for
review see ref. {1541}.
TP53 and microsatellite instability and
treatment response
Immunohistochemistry demonstrates a
high level of wild type TP53 protein in
TGCTs. However, inactivating mutations
are hardly found. This led to the view that
high levels of wild type TP53 might
explain the exquisite chemosensitivity of
TGCTs. However, it has been shown that
this is an oversimplification [{1301}, for
review], and that inactivation of TP53
explains only a minority of treatment
resistant TGCTs {1129}. In fact, the overall
sensitivity of TGCTs might be related
to their embryonic origin, in contrast to
the majority of solid cancers.
Chemoresistance of seminomas and
non-seminomas has been related to high
level genomic amplifications at 1q31-32,
2p23-24, 7q21, 7q31, 9q22, 9q32-34,
15q23-24, and 20q11.2-12 {2147}. The
XPA gene, involved in DNA repair, maps
to 9q22. Low expression of XPA has
been related to the sensitivity of TGCT to
cisplatin based chemotherapy {1342},
possibly due to a reduced nucleotide
excision repair. A high expression of the
DNA base excision repair has been
suggested for chemoresistance in
TGCTs {2212}. Another mechanism of
resistance against cisplatin is interruption
of the link between DNA damage
and apoptosis. The mismatch repair
pathway (MMR) is most likely involved in
the detection of DNA damage, and initiation
of apoptotic programs rather than
Fig. 4.08 Microsatellite instability (MSI) at locus D2S123 in a series of refractory germ cell tumours of the
adult. Shown are the results in normal peripheral blood DNA (indicated by "N") and matched tumour DNA
("T"). The underlined cases show MSI.
repair. Disturbed MMR, apparent from
microsatellite instability (MSI), is a frequent
finding in cisplatin refractory nonseminomas
{1652}, but not in TGCTs in
general {603,1561,1652,1857,2044}.
However, so far, immunohistochemical
demonstration of MMR factors cannot
predict MSI in these cancers.
Expression profiles
Three independent studies using array
DNA and cDNA CGH on TGCTs have
been reported. The first {2436} showed
that gene expression profiling is able to
distinguish the various histological types
of TGCTs using hierarchical cluster
analysis based on 501 differentially
expressed genes. In addition, it was
found that the GRB7 and JUP genes are
overexpressed from the long arm of chromosome
17 and are therefore interesting
candidates for further investigation. The
other two studies focus on the short arm
of chromosome 12, i.p. the p11.2-p12.1
region. That this region is indeed of interest
is demonstrated by the finding that
TGCTs without a restricted 12p amplification
do show preferential overexpression
of genes from this region {2219}. Two
putative candidate genes (related to the
ESTs Unigene cluster Hs.22595 and
Hs.62275) referred to as GCT1 and 2
genes were identified to be overexpressed
in TGCTs {300}. However, these
candidates map outside the region of
interest as found by earlier studies and
are expressed ubiquitously. The second
study on 12p {2219}, reports that BCAT1
is an interesting candidate for non-seminomas
specifically, while a number of
candidates were identified within the
region of interest on 12p, including EKI1,
and amongst others a gene related to
ESTs AJ 511866. Recent findings indicating
specific regions of amplification
within the amplicon itself {1545,2915} will
facilitate further investigation of the
gene(s) involved.
Animal models
A number of animal models have been
suggested to be informative for the development
of TGCTs, like the mouse teratocarcinoma
{1580,1581,2771}, the seminomas
of the rabbit {2717}, horse {2716},
and dog {1539}, as well as the HPV-
{1351}, and more recently the GDNF
induced seminomatous tumours in mice
{1712}. However, none of these include
all the characteristics of human TGCTs,
like their origin from IGCNU, embryonic
characteristics, their postpubertal manifestation,
and the possible combination of
seminoma and non-seminoma.
Therefore, data derived from these models
must be interpreted with caution in the
context of the pathogenesis of TGCTs.
However, the mouse teratocarcinomas
and canine seminomas, are most likely
informative models for the infantile teratomas
and yolk sac tumours and the
spermatocytic seminomas, respectively.
Germ cell tumours 227