2009 Vienna - European Society of Human Genetics

Cancer genetics
tion (PAX5 and GATA5), and cell-to-cell communication (CD44), their
epigenetic silencing could play an important role in RB initiation and
progression. Therefore this study not only confirms the importance of
MGMT inactivation, but also identifies new interesting candidate genes
for RB. Aberrant methylation of these factors could play a key role in
tumour development especially in bilateral cases, where chromosomal
imbalances are less frequently observed.
P06.085
An sdhd knockout mouse shows no evidence of paraganglioma
or pheochromocytoma tumor development but does exhibit
peripheral ventilatory insufficiency
J. P. Bayley, L. Teppema, P. C. W. Hogendoorn, P. Devilee, A. Dahan, P. E. M.
Taschner;
Leiden University Medical Center, Leiden, The Netherlands.
SDHD is a human tumor suppressor gene and a subunit of succinate
dehydrogenase, a component of both the TCA cycle and the electron
transport chain.
Here we describe a mouse KO of Sdhd as a model for pheochromocytoma/paraganglioma
with 30 month-follow up, and as a model for
carotid body-mediated peripheral ventilatory insufficiency.
The absence of live homozygote (-/-) offspring indicates that complete
loss of Sdhd results in embryonic lethality. Knockout of the Sdhd gene
did not lead to tumor development at any stage of the normal lifespan
of these mice, in contrast to the highly penetrant phenotype in humans.
A single Sdhd +/- mouse showed unilateral 5-fold hyperplasia of the
carotid body.
Sdhd +/- mice showed no gross physical abnormalities, similar body
and organ weights to wildtype mice, and no genotype-related pathology.
The ultrastructure of the carotid body and adrenal mitochondria
was normal.
Breathing in small animals is regulated by central chemoreceptors located
in the ventral medulla, and the peripheral chemoreceptors in the
carotid bodies.
The carotid body is essential to the peripheral ventilatory response,
and loss of SDHD may affect carotid body function. We found that the
carotid body-related ventilatory response, the so-called peripheral response,
is indeed compromised. We show that while the central CO 2 -
driven ventilatory response was intact in both wildtype and Sdhd+/-
mice, the CO 2 -driven peripheral ventilatory response was severely
compromised in Sdhd+/- mice.
P06.086
Differential repair of UVA versus UVB-induced cyclobutane
pyrimidine dimers in the genome of human keratinocytes
M. Karbaschi, M. D. Evans, M. S. Cooke;
University of Leicester, Leicester, United Kingdom.
Worldwide, one in three cancers is skin-related and the WHO expects
the skin-cancer epidemic to increase. Solar ultraviolet radiation (UVR)
by inducing DNA photo-lesions, has become the prime cause of most
skin cancers. These cancers could be prevented if we protect ourselves
from UVR.
UVR comprises three main regions: UVC is absorbed by the ozone
layer and does not affect the skin. UVB is directly absorbed by DNA
and induces different forms of lesions like cyclobutane pyrimidine
dimers (CPDs). In contrast with UVB, UVA is indirectly absorbed by
DNA. UVA is suspected to play a key role in induction of skin tumors
and may be even more important than UVB in mutagenesis. CPDs
have been found to be induced in human skin cells exposed to UVA
through a different mechanism but the mechanism of CPD induction by
UVA is not clearly identified. Most sunscreens filter out UVB absorption,
but they cannot block most of UVA, so they do not help to prevent
skin cancer.
A better assessment of the routes by which UVA and UVB induce
CPDs in DNA, may lead to prevention of skin cancer. For this purpose
in the present study by use of the highly sensitive single cell gel electrophoresis
(comet assay) formation and repair rate of UVA-induced
CPDs versus UVB-induced CPDs was compared.
Despite seeing a 10-fold greater dose of UVA, UVB induction of CPD
was significantly greater. However, the rate of UVA-induced CPD repair
appeared to be faster than the rate of UVB-induced CPD repair.
P06.087
Diverse functions of slug, a master regulator of Emt, in prostate
cancer cell lines
M. Emadi Baygi 1,2 , Z. S. Soheili 3 , A. Dizaji 4 , W. A. Schulz 5 ;
1 Tarbiat Modares University, Tehran, Islamic Republic of Iran, 2 Shahrekord
University, Shahrekord, Islamic Republic of Iran, 3 National Institue of Genetic
Engineering and Biotechnology, Tehran, Islamic Republic of Iran, 4 National
Institute of Genetic Engineering and Biotechnology, Tehran, Islamic Republic of
Iran, 5 Heinrich Heine University, Dusseldorf, Germany.
The transcription factor Slug (SNAI2) is capable of mediating the epithelial-mesenchymal
transition (EMT), which is thought to be a crucial
step in metastasis. There is moreover increasing evidence that this
factor has additional functions in tumor progression. We have investigated
the effects of siRNA-mediated down-regulation (knockdown) of
Slug in prostate cancer cell lines.
Among the prostate carcinoma cell lines, PC-3 and PC3-16 subline
(kindly provided by the Homburg DPKK group) show the moderate and
highest expression of Slug. Therefore, Slug knockdown was performed
in PC-3 and PC3-16 cells. In each line, efficient down-regulation at the
mRNA and protein level was achieved.Long-term knock-down of Slug
expression induced a severe decline in cell proliferation in both cell
lines, with a prominent G0/G1 arrest in PC3-16 cells. Apoptosis was
slightly enhanced in PC-3 cells only. SNAI2 siRNA-treated cells did
not tolerate detachment from the culture plates, probably due to downregulation
of integrin α6β4. Moreover, suppression of Slug expression
strongly abolished invasiveness of PC-3 cells. Finally, knock-down of
Slug expression disturbed both the microtubule and actin cytoskeletons
resulting in grossly enlarged cells with a jellyfish-like phenotype.
Together, these data suggest that the most pertinent function of Slug
in the prostate cancers that express it, is to act as a regulator of cell
adhesion and cell shape maintenance.
P06.088
the association of 5a-Reductase type 1 with HBV positive
hepatocellular carcinoma (Hcc) risk in male chinese
N. L. Tang 1,2 , J. Jiang 1 , W. Yeo 3 , P. Lai 4 ;
1 Department of Chemical Pathology,The Chinese University of Hong Kong,
Hong Kong, China, 2 Laboratory of Genetics of disease susceptibility ,Li Ka
Shing Institute of Health Sciences, Hong Kong, China, 3 Department of Clinical
Oncology, The Chinese University of Hong Kong, Hong Kong, China, 4 Department
of Surgery, The Chinese University of Hong Kong, Hong Kong, China.
Introduction: Epidemiological studies suggested that male predominance
of hepatitis B positive hepatocellular carcinoma was associated
with serum levels of androgens. Although androgen levels are believed
to be influenced by genetic factors, there is no definitive information to
indicate which genetic variations in the androgen metabolic pathway
are associated with the risk of hepatocellular carcinoma (HCC) development.
Aim: The aim of the present study was to study polymorphisms in
SRD5A1, a gene related to androgen metabolic pathway in converting
testosterone to its more potent biological form, dehydrotestosterone
(DHT),and their association with HCC.
Methods: 300 HBV positive HCC male patients and 2000 male Chinese
population controls were recruited in this study. Using the International
HapMap Phase II data on the Han Chinese (CHB) cohort,
3 tagging SNPs (rs248807, rs11738248, rs824811) were selected by
spectral analysis. Genotyping of these three SNPs was performed using
Allele Specific Tm-shift PCR method.
Results and conclusion: The genotype frequencies of rs248807,
rs11738248, rs824811 followed Hardy Weinberg equilibrium (p>0.05).
The SNP rs11738248 was significantly associated with HCC
(X 2 =10.069, P=0.007) while the association for SNP rs248807 was
modest. However, the SNP rs824811 was not in association with HCC
(X 2 =0.54, P=0.763). All the result suggests that SRD5A1 gene may associate
with the development of HCC in men. We previously showed
that SRD5A2 isoenzyme was associated with HCC. The results on
another isoenzyme SRD5A1 presented here further confirmed the role
of androgen metabolites in the carcinogenesis of HBV related HCC.