2008 Barcelona - European Society of Human Genetics

Cancer genetics
there are no changes in the amount of mtDNA . We have also observed
a significance decrease in the expression of mitochondria-encoded
genes MT-12S, MT-CO2 and MT-ATP6 .
Supported by MEC (SAF 2005-00166), and Generalitat de Catalunya
(2006 SGR 00018)
P04.188
Identification of novel molecular targets for arresting prostate
cancer cell proliferation.
S. F. Gaudi1 , F. Carlini1 , D. De Orsi1 , S. Paradisi1 , G. Bozzuto1 , L. Toccacieli1 , G.
Formisano1 , A. Weisz2 , R. Arcieri1 , S. Vella1 ;
1 2 Istituto Superiore di Sanità, Roma, Italy, Seconda Università degli Studi di
Napoli, Naple, Italy.
Retroelements (RE) represent a significant portion of the human genome
(45 %) and play a key role in the regulation of gene expression
in mammals . RE can act as insertional mutagens altering the coding
integrity of genes and, particularly the gene coding for reverse transcriptase
(RT) is tipically expressed at high level in transformed cells
and tumor .
A large body of published data supports the conclusion that retrotransposons
are biologically active elements and indicates that retrotransposition
is an ongoing process in mammalian genomes and can trigger
the onset of several pathologies including cancer . Active LINE-1 transcripts
have been detected in murine embryonal carcinoma cells and
in human testicular cancers, while only basal levels of RT activity have
been revealed in terminally differentiated cells and tissues .
Studies developed in our research groups over the last years have
shown that the commercially available RT inhibitor, Abacavir, widely
used in AIDS therapy, is able to modulate cell growth and differentiation
in prostate cancer cell line (PC3) .
ABC, respectively at 10 and 100 μg/ml, is able to reduce proliferation,
migration and invasion. We studied genome wide expression profile on
PC3 cells treated with ABC and we identified genes involved in RNA
regulation and expression. Further immuno-fluorescence experiments
revealed a critical involvement of nucleolus as target of ABC action .
Finally, we discuss new approaches to treatment, including recently
discovered molecular targets that might provide more effective treatment
strategies with the potential for less toxicity .
P04.189
PtcH1 gene polymorphisms and risk of non melanoma skin
cancer after organ transplantation
A. Begnini 1 , G. Tessari 2 , M. Gomez Lira 1 , L. Naldi 2 , G. Remuzzi 2 , L. Boschiero 2 ,
A. Forni 2 , C. Rugiu 2 , S. Piaserico 2 , G. Girolomoni 2 , A. Turco 1 ;
1 Section of Biology and Genetics, Department of Mother and Child and Biology–Genetics,
University of Verona, Verona, Italy, 2 Section of Dermatology,
Department of Biomedical and Surgical Science, University of Verona, Verona,
Italy.
Organ transplant recipients (OTR) are at higher risk of non melanoma
skin cancer (NMSC), particularly basal cell carcinoma (BCC) and
squamous cell carcinoma (SCC) . Risk factors for NMSC in OTR include
skin type, ultraviolet light exposure, immunosuppression, human
Papilloma virus infections, and genetic susceptibility .
PTCH1 is a negative regulator of the Hedgehog pathway, that provide
mitogenic signals to basal cells in skin . PTCH1 gene mutations are responsible
for nevoid basal cell carcinoma syndrome (NBCCS or Gorlin
syndrome), and also occur in sporadic forms of BCC . Associations
have been demonstrated between PTCH1 polymorphisms and BCC
susceptibility in non transplanted recipients .
This study was designed to investigate if known polymorphisms of
PTCH1 gene contribute, individually or as haplotypes, to NMSC risk
after transplantation, and to identify novel genetic polymorphism in the
proximal 5’ regulatory region of the gene .
We analyzed the frequencies of three PTCH1 gene SNPs (rs2297086,
rs2066836, rs357564) in 273 Northern Italian OTR patients (120 cases
and 153 controls) .
Single locus and haplotype frequency analysis showed no significant
associations .
Screening for polymorphisms was performed by heteroduplex analysis
in 30 cases and 30 matched controls .
Two polymorphisms, -198A>G and -195G>C, were identified in the
5’ flanking region. Both variants were in linkage disequilibrium and
showed a frequency of 0 .5% (2/400) in 200 tested individuals .
These results seem to exclude an important role of the PTCH1 gene in
NMSC susceptibility after organ transplantation . Further studies on a
larger sample are warranted to confirm these findings.
P04.190
molecular genetic and clinical survey of swiss PtEN hamartoma
tumor syndrome patients
M. Plasilova 1 , N. Boesch 1 , C. Egenter 1 , B. Röthlisberger 2 , H. Mueller 1 , K. Heinimann
1 ;
1 Research Group Human Genetics, Division of Medical Genetics UKBB, Center
of Biomedicine, University Children’s Hospital, Basel, Switzerland, 2 Center of
Laboratory Medicine, Cantonal Hospital Aarau, Aarau, Switzerland.
PTEN hamartoma tumor syndrome (PHTS) is a condition caused by
germline mutations in the PTEN (phosphatase with tensin homology)
tumor suppressor gene which encodes a phosphatase with lipid and
protein specificity, a negative regulator of the phosphoinositol 3-kinase
(PI3K) pathway . PHTS includes Cowden syndrome (CS), Bannayan-
Riley-Ruvalcaba syndrome (BRRS), Proteus syndrome (PS), and Proteus-like
syndrome, the first two being the most prevalent conditions.
Here we present the results of a molecular genetic and clinical survey
on 12 Swiss PHTS patients (10 CS, 2 BRRS) and their relatives referred
during the past 4 years . All patients were subjected to DNA sequencing
of the coding (incl .exon/intron boundaries) and the promoter
region, and to gene dosage analysis . In the coding region of PTEN,
heterozygous germline mutations were identified in five CS patients
and one BRRS patient . The majority of the PTEN mutations were
found to be either nonsense point mutations or frameshift deletions .
In addition, one heterozygous splice site mutation and one missense
mutation were observed. Based on these findings, the mutational
spectrum and clinical manifestations in both, PTEN mutation carriers
and those without detectable genetic alterations will be presented . In
particular, the clinical overlap between CS and BRRS PTEN mutation
carriers will be discussed .
P04.191
Evaluation of exon 2 and exon 6 mutaions of PtEN gene in
patients with gastric cancer
A. Kalaycı 1 , T. Cora 2 , H. Toy 3 , H. Acar 4 , E. Kurar 5 ;
1 Dept. of Arkeology, S.Univ, Science Fakulty, Konya, Turkey, 2 Dept. of Medical
Genetics, Selcuk Univ. Medical Faculty, Konya, Turkey, 3 Dept. of Pathology,
S.Ü. Medical Faculty, Konya, Turkey, 4 Dept. of Medical Genetics, S.University,
Medical Faculty, Konya, Turkey, 5 Dept. of Zootekni, S.Univ, Veterinary Fakulty,
Konya, Turkey.
Gastric cancer (GC) is still one of the most frequent causes of cancerrelated
deaths in all overworld . Molecular mechanism of GC has not
been well described . In recent years, the pathogenesis of GC related
to the basis of the molecular and genetic changes have been investigated
in the different populations. These changes can be classified as
activation of oncogenes, the inactivation of tumor suppressor genes,
the reduction of cellular adhesion, the reactivation of telomerase and
the presence of microsatellite instability . A novel tumor supressor
gene, PTEN (phosphatase and tensin homologue deleted on chromosome
ten), has recently been described and mapped to chromosome
band 10q23 .3 region . In the present study, we evaluated the frequency
of exon 2 and exon 6 mutaions of PTEN gene in the normal (n=47) and
tumor tissues (n=47) of the patients with GC, by using SSCP and sequencing
techniques . The frequency of mutations in exon 2 and exon
6 of the PTEN gene in tumor and normal tissue DNAs were compared
and the results were compared with the other results published for the
other population in the literature .
P04.192
High throughput, nanofluidic real-time PCR analysis of gene
expression in tumor samples
E. Ortenberg, S. Liu-Cordero, J. Hurley, T. Morrison, J. Cho, M. Kopczynski, C.
Brennan, K. D. Munnelly;
BioTrove, Inc., Woburn, MA, United States.
Understanding biological complexity arising from patterns of gene expression
and gene function requires accurate and precise measurement
of RNA levels across large numbers of genes simultaneously .
We demonstrate a novel highly parallel, nanofluidic system capable of
performing 3072 real-time polymerase chain reactions (rt-PCR), based
on Sybr Green detection, in a miniaturized through-hole array format .