2009 Vienna - European Society of Human Genetics

Cancer genetics
P06.005
tiling resolution array-based comparative genomic hybridisation
analyses of acute lymphoblastic leukaemias in children with
Down syndrome reveal recurrent gain of 8q and deletions of 7p
and 9p
C. Lundin1 , J. Davidsson1 , L. Hjorth2 , M. Behrendtz3 , B. Johansson1 ;
1 2 Dept of Clinical Genetics, Lund, Sweden, Dept of Pediatrics, Lund, Sweden,
3Dept of Pediatrics, Linköping, Sweden.
Down syndrome (DS) is a risk factor for childhood acute leukemia, with
a cumulative risk of 2.1% at the age of 5 years. Acute lymphoblastic
leukemia (ALL) is the most prevalent form, constituting 60% of new
cases.
A total of 286 pediatric B-ALLs have been cytogenetically analyzed
at our department. Ten (3.5%) were DS-ALL and DNA was available
for array CGH analysis in seven of these. Using G-banding, acquired
changes were detected in five of the cases. None of these aberrations
were recurrent. However, by the use of the 32K platform, the following
recurrent genomic imbalances were observed: del(2)(p11.2p11.2),
gain of 8q and deletions of 7p and 9p.
The minimally deleted region in 7p occurred at 7p12, which was lost
in two of our cases as well as in three DS-ALLs from the literature.
Regarding the 9p deletions, the focal deletions of CDKN2A and PAX5
previously reported might well correspond to the deletions encompassing
9p11.2-22.3 in two of our cases and the common deleted segment
9p13-p22 in two further cases of DS-ALL recently published. An intriguing
finding of the present study was a deletion of 12q in one case,
comprising KITLG in 12q21.3. In adults, this gene has been described
to function in hematopoiesis.
Thus, some interesting regions and specific genes have recently been
identified in acute leukemias in children with Down syndrome and
more high resolution studies are clearly needed to evaluate these findings
and to clarify further the molecular genetic picture in this patient
cohort.
P06.006
investigation the correlation of Phenotypes with the Genotypes
of the AAt in Esophageal squamous cell carcinoma (sccE)
S. Mohammad Ganji1 , F. Rastgar-Jazii1 , A. Sahebghadam-Lotfi1,2 , M. Yazdanbod3
, A. Mota2 , A. Mohsenifar2 ;
1 2 NIGEB, Tehran, Islamic Republic of Iran, Biochemistry Department, Tarbiat
moddares University, Tehran, Islamic Republic of Iran, 3Madaen Hospital, Tehran,
Islamic Republic of Iran.
Proteolytic enzymes such as Alpha-1 antitrypsin (AAT) play significant
role in malignancy including Loss of growth regulation, invasiveness
and metastases. AAT is the most abundant serin protease inhibitor
in human plasma which produced mainly in liver and monocytes and
deficiency of it, is an inherited disorder characterized by reduced serum
level of AAT. The most common deficient genotypes of AAT are
Protease inhibitors Z(PiZ) and S(PiS). The association of deficient AAT
subtypes with several tumors such as primary liver carcinoma, lung
cancer, gastrointestinal cancer and malignant hepatoma was reported.
This study aims to test relationship between AAT phenotypes and genotypes
Z and S with Esophageal Squamous Cell Carcinoma (SCCE)
cancer in patients whom were attending Madaen Hospital, in Tehran,
during 2006-2007. Serum and DNA were isolated from 37 patients and
Isoelectricfocusing was carried out on serum samples. Genotypes of
S and Z alleles were performed by RFLP technique using TaqI restriction
enzyme. Our results indicated that the mean range for TIC and
AAT by nephlometry test of patients were significant difference rather
than healthy peoples (P0.05). In conclusion, we can report a relationship
between AAT deficient genotypes S and esophageal cancer in
the studied patients.
P06.007
mutations of Hh-Gli signaling Pathway Genes in Basal cell
carcinomas (Bccs)
V. Musani 1 , M. Cretnik 1 , M. Levacic Cvok 1 , P. Ozretic 1 , M. Situm 2 , D. Leovic 3 , S.
Levanat 1 ;
1 Rudjer Boskovic Institute, 10002 Zagreb, Croatia, 2 Department of Dermatovenerology,
Clinical Hospital “Sestre milosrdnice”, University of Zagreb, 10000
Zagreb, Croatia, 3 Department of Maxillofacial Surgery, Clinical Hospital Osijek,
31000 Zagreb, Croatia.
Basal cell carcinoma (BCC) of the skin is the most common human
cancer, and shows a continuously increasing incidence. BCCs occur
predominantly on sun-exposed skin of elderly fair-skinned people.
Several tumor suppressor genes and oncogenes have been implicated
in the pathogenesis of BCCs, most of them beeing members of the
Hedgehog-Gli (Hh-Gli) signaling pathway.
Hh-Gli signaling pathway is one of the fundamental signaling pathways
in embryonic development and is required in vertebrates for normal
development of many structures, including the neural tube, axial skeleton,
skin and hair.
Normally, a secreted protein Hedgehog (Hh) binds to a transmembrane
protein Patched (Ptch), which causes release of another transmembrane
protein Smoothened (Smo) from its repression by Ptch. This
triggers a signaling cascade in the cytoplasm which leads to translocation
of the activated transcription factor Gli to the nucleus and expression
of target genes (Gli, Ptch, WNT and TGF beta family members,
various cyclins), involved in cell proliferation, while Ptch acts as a limiting
factor by blocking pathway activity.
Aberrant activation of the pathway in adult tissue is associated with the
development of various tumors (BCC, medulloblastoma, pancreatic,
gastrointestinal etc ).
In our research we investigated mutation status of several Hh-Gli pathway
genes in sporadic BCCs. The mutation screening was performed
by high resolution melting approach, which is based on differences in
melting curves caused by variations in nucleotide sequence; detected
variants were confirmed by direct sequencing.
Our results show mutations in several pathway members (SHH, PTCH,
SUFU) implicating their involvement in tumor pathogenesis.
P06.008
the intracellular localization of folliculin (FLcN) in Birt-Hogg-
Dubé syndrome
M. Vreeburg 1 , T. Claessens 2 , D. Marcus-Soekarman 1 , M. van Geel 2 , M. A. M.
van Steensel 2,3 ;
1 University hospital Maastricht, department of clinical genetics, Maastricht, The
Netherlands, 2 University hospital Maastricht, department of dermatology, Maastricht,
The Netherlands, 3 Research Institute Growth & Development (GROW),
University Maastricht, Maastricht, The Netherlands.
Birt-Hogg-Dubé syndrome (MIM 135150 ) is an autosomal dominant
disorder characterized by benign hair follicle tumors, pneumothorax
and kidney malignancies. It is caused by nonsense mutations and deletions
affecting the BHD gene encoding for folliculin (FLCN). FLCN
is thought to be a negative regulator of mTOR (mammalian Target Of
Rapamycin), a central player in cellular responses to growth signals.
Two binding partners ( FNIP1 and FNIP2) are known. FNIP1 may interact
with AMPK, a kinase upstream of mTOR. Not much is known
about FLCN’s binding partners or manner of interaction with the mTOR
network. FLCN is supposed to be a cytoplasmic protein, but it is known
that many proteins shuttle between cellular compartments as part of
their normal function. In order to more fully understand its function,
we decided to study FLCN’s subcellular localization in more detail because
it might be possible that mutations affect FLCN’s localization
and, in that way, its function.
To examine how FLCN’s subcellular localization is influenced by mutations
and/or by culture conditions that influence mTOR signalling we
have prepared N-terminal EGFP-tagged FLCN expression construct
(CMV promotor). Using site directed mutagenesis, we introduced several
known mutations into the contructs. These constructs and a wild
type were transfected into HEK293 cells and followed by fluorescence
microscopy. Next, we repeated the experiments under conditions
known to influence mTOR signaling: hypoxia, starvation and rapamycin
administration to see if mutations affect FLCN’s response to these
alterations in the environment. Results from these experiments will be
presented.
P06.009
Evaluating the expression of Bmi1 gene and protein in bladder
tumors by means of Rt-PcR and immunohistochemistry
M. Malekzadeh Shafaroudi 1 , A. Malekzadeh 2 , S. J. Mowla 2 , A. R. Bahrami 3 ;
1 Sari Medical Faculty, Sari, Islamic Republic of Iran, 2 Tarbiat Modares University,
Tehran, Islamic Republic of Iran, 3 Institute of Biotechnology, Ferdowsi Uni-