CHAPTER X CHAPTER 4 - Cancer et environnement

Similar tumours as those of group 1 and
2 can be found in the ovary and extragonadal
sites, in particular along the midline
of the body. Relatively little is known
on the genomic changes of these GCTs.
Supposedly the findings in the GCTs of
the testis are also relevant for classification
and understanding of the pathogenesis
of ovarian and extragonadal GCTs.
Genetic susceptibility (familial tumours)
Familial testicular germ cell tumours of
adolescents and adults (TGCTs), account
for 1.5-2% of all germ cell tumours of
adults. The familial risks of TGCTs
increase 3.8-fold for fathers, 8.3 for brothers
and 3.9 for sons indicating that genetic
predisposition is a contributor to testicular
cancer {532}. Earlier age of onset, a
higher frequency of bilaterality and an
increased severity of disease suggest
that genetic anticipation is responsible
for many father-son TGCTs {1014}.
Recently, environmental and heritable
causes of cancer have been analysed by
structural equation modelling {532}. The
estimate of proportion of cancer susceptibility
due to genetic effects was 25% in
adult TGCTs. The childhood shared environmental
effects were also important in
testicular cancer (17%).
Numerous groups have attempted to
identify candidate regions for a TGCT
susceptibility gene or genes {1386,1457,
2148,2435}. No differences were detected
between familial/bilateral and sporadic
TGCT in chromosomal changes {2435}.
However, a TGCT susceptibility gene on
chromosome Xq27, that also predisposes
to undescended testis, has been proposed
by the International Testicular
Cancer Linkage Consortium {2148}.
Although the role of genetic factors in the
etiology of TGCTs appears to be established,
the existence of a single susceptibility
gene is doubtful. Most probably
genetic predisposition shared with
intrauterine or childhood environmental
Table 4.03
Tumour suppressor genes involved in the pathogenesis of testicular germ cell tumours (TGCTs).
(Putative) Pathway Gene Chromosomal
mapping
Cell cycle control
Cell survival/
Apoptosis
Transcription
Signaling
Methylation
Proteolysis
Protein interaction
Unknown
CDKN2C
CDKN1A
CDKN2B
CDKN2A
CDKN1B
RB1
CDKN2D
BCL10
FHIT
TP53
MXI1
WT1
APC
MCC
NME1,2
DCC
SMAD4
1p32
6p21
9p21
9p21
12p12-13
13q14
19p13
1p22
3p14
17p13
10q24
11p13
5q21-22
5q21-22
17q23
18q21
18q21
RNF4 4p16.2 {2055}
hH-Rev107 11q12-13 {2407}
{175}
{175}
{1053}
{417,1041,1053}
{175}
{2519}
{176}
{740,2703,2829}
{1384}
{1301} (for review)
{2436}
{1536}
{2045}
{2045}
{161}
{1856,2516}
{299}
DNMT2 10p15.1 {2436}
Testisin
KALK13
NES1/KLK10
16p13
19q13
19q13
Reference(s)
{1116}
{409}
{1577}
effects are involved in the molecular
pathogenesis of TGCTs.
Inter-sex individuals
Persons with 46,XY or 45,X/46,XY
gonadal dysgenesis are at very high risk
of gonadal germ cell tumour. The
absolute risk is reported to be as high as
10-50% {2267,2728}.
Genomic imprinting
Genomic imprinting refers to the unique
phenomenon in mammals of the different
functionality of a number of genes due to
their parental origin. This difference is
generated during passage through the
germ cell lineage. The pattern of genomic
imprinting has significant effects on
the developmental potential of cells
{2459}. TGCTs show a consistent biallelic
expression of multiple imprinted genes
{882,1537,1544,1742,1914,2129,2697,2
726} as do mouse embryonic germ cells
{2548}. This suggests that biallelic
expression of imprinted genes in TGCTs
is not the result of loss of imprinting (LOI)
but is intrinsic to the cell of origin. This
could also explain the presence of telomerase
activity in TGCTs, except in
(mature) teratomas {53}. The teratomas
and yolk sac tumours of infants show a
slightly different pattern of genomic
imprinting {2243,2334}, supporting the
model that these tumours originate from
an earlier stage of germ cell development
than TGCTs. Although little is known
about the pattern of genomic imprinting
of spermatocytic seminomas {2726} the
available data indicate that these
tumours have already undergone paternal
imprinting.
Testicular germ cell tumours of
adolescents and adults:
Seminomas and non-seminomas
Chromosomal constitution
All TGCTs, including their precursor,
intratubular germ cell neoplasia unclassified
(IGCNU) are aneuploid [{567,676,
1962}, for review]. Seminoma and IGCNU
cells are hypertriploid, while the tumour
cells of non-seminoma, irrespective of
their histological type are hypotriploid.
This suggests that polyploidization is the
initial event, leading to a tetraploid
IGCNU, followed by net loss of chromosomal
material {1962}. Aneuploidy of
TGCTs has been related to the presence
of centrosome amplification {1653}.
224 Tumours of the testis and paratesticular tissue