2008 Barcelona - European Society of Human Genetics

Cancer genetics
controls, by heteroduplex analysis . We analyzed sequences containing
binding sites for stabilization elements and putative sequences of
microRNAs binding sites . One polymorphism was found (rs4648290)
which is located in a microRNA binding site . Genotyping of this variant
is ongoing and functional effects will be analized .
P04.171
copy Number Alterations of HER and EGFR Genes in Nonsmall
cell Lung cancer (NscLc)
M. Ozdemir 1 , P. Uludag 1 , A. Uludag 1 , B. Durak 1 , N. Buyukpinarbasili 2 , E. Tepeli
1 , S. Artan 1 ;
1 Eskisehir Osmangazi University, Medical Faculty, Department of Medical
Genetics, Eskisehir, Turkey, 2 Istanbul Yedikule Chest Disease Hospital, Department
of Pathology, Istanbul, Turkey.
PURPOSE: Epidermal Growth Factor Receptor (EGFR) and HER2 are
the members of EGFR family . They are transmembrane proteins with
tyrosine kinase activity. EGFR and HER2 amplification and/or overexpression
have been reported in several types of cancer . The study was
performed to correlate copy number variations of HER2 and EGFR
genes with histopathological features of NSCLC samples . MATERI-
ALS-METHODS: Copy number status of the genes was assesed using
FISH in 100 archivial materials . RESULTS: 75 % of the samples
successfully analysed by FISH. HER2 amplification was only detected
in high grade tumors whereas EGFR amplification was significantly
seen in high grade (16/75) tumors but also less frequently detected
in low-grade samples. Both of the gene amplifications were detected
in histologically proved squamous cell and adenocarcinoma tumors in
about equal frequencies. Amplification of EGFR also correlated with
smoking. CONCLUSION: The amplification of EGFR and HER2 in
NCLSC patients may play important role in the pathogenesis of lung
carcinoma .
P04.172
Studying Amplification Status of HER2/NEU and EGFR
Oncogenes in Non-small cell Lung cancers by Real-time PcR
technique
M. H. Muslumanoglu 1 , D. Uzun 1 , O. Cilingir 1 , M. Ozdemir 1 , N. Buyukpinarbasili
2 , E. Tepeli 1 , S. Artan 1 ;
1 Eskisehir Osmangazi University, Medical Faculty, Department of Medical
Genetics, Eskisehir, Turkey, 2 Istanbul Yedikule Chest Disease Hospital, Department
of Pathology, Istanbul, Turkey.
AIM: Family members of Epidermal growth factor receptor, EGFR and
Her2/neu oncogenes, code transmembran proteins which exhibit tyrosine
kinase activity . The family members play major roles in signal
transducing pathways. Amplification /overexpression of these protooncogenes
have been identified in various cancer types including NSCLC.
The study was performed to correlate copy number variations of HER2
and EGFR genes with histopathological features of NSCLC samples,
smoking status and family histories of the cases . MATERIALS-METH-
ODS: DNAs were extracted from formalin-fixed, paraffin-embedded
sections obtained from 100 patients with NSCLC and amplification levels
of HER2 and EGFR were assesed by real-time PCR . RESULTS:
The HER2/neu and EGFR gene amplifications were measured quantitatively
in 18% and 26% of tumors, respectively . HER2 and EGFR
amplifications were significantly detected in high grade tumors and
HER2 gene amplification was only seen in tumors of smoking cases.
Amplification of EGFR also correlated with smoking. CONCLUSION:
The amplification of EGFR and HER2 in NCLSC patients may play
important role in the pathogenesis of lung carcinoma . Real-time PCR
is easy to operate and deserves widespread application for detection
of HER2 and EGFR gene copy number variations .
P04.173
Participation of OCT3/4 and β-Catenin during dysgenetic
gonadal malignant transformation
G. Queipo, I. Palma, S. Kofman-Alfaro;
Hospital General de Mexico-Facultad de Medicina Universidad Nacional
Autónoma de México SDEIPTID05-1, Mexico City, Mexico.
Gonadoblastoma (GB) is an in situ germ cell tumor, 30% of patients
GB develops in dysgerminoma/seminoma . GB almost exclusively affects
a subset of patients with Disorders of sex development (DSD),
in which tumor development is associated with the presence of an
extra Y-chromosome (either normal or abnormal), or with molecular
evidence for Y-derived sequences . GB in dysgenetic gonads and its
counterpart, carcinoma in situ (CIS) in well-differentiated testicular tissue,
may be the earliest stages in the development of malignant germ
cell tumors (GCTs) . Although the mechanisms that trigger neoplastic
progression are still unknown, several pathways have been proposed .
Abnormal OCT3/4 expression is the most robust risk factor for malignant
transformation . This transcription factor regulates the pluripotency
of embryonic stem cells and is necessary for the survival and migration
of primordial germ cells and has been associated with the germ
cell neoplastic process. OCT3/4 and β-catenin might both be involved
in the same oncogenic pathway, both genes are master regulators of
cell differentiation and overexpression of either gene may result in
cancer development. The mechanism by which β-catenin participates
in GB transformation is not completely clear . In an effort to elucidate
the participation of β-catenin and E-cadherin, as well as OCT3/4, in
the GB oncogenic pathways, we analyzed those molecules in seven
patients with mixed gonadal dysgenesis and GB . Proposing that the
proliferation of immature germ cells in GB may be due to an interaction
between OCT3/4 and accumulated β-catenin in the nuclei of the
immature germ cells .
P04.174
An inherited mitochondrial DNA disruptive mutation
preferentially selected in oncocytic tumor cells
G. Gasparre 1 , L. F. Pennisi 1 , L. Iommarini 2 , A. M. Porcelli 3 , M. Lang 1 , G. Ferri 4 ,
I. Kurelac 1 , A. Ghelli 3 , E. Bonora 1 , C. Ceccarelli 5 , M. Rugolo 3 , N. Salfi 5 , G. Romeo
1 , V. Carelli 2 ;
1 Unità Operativa Genetica Medica, Bologna, Italy, 2 Dipartimento di Scienze
Neurologiche - University of Bologna, Bologna, Italy, 3 Dipartimento di Biologia
Evoluzionistica Sperimentale, University of Bologna, Bologna, Italy, 4 Dip. Sc.
Chirurgiche Specialistiche ed Anestesiologiche-Policlinico Sant’Orsola Malpighi,
Bologna, Italy, 5 U.O.Anatomia e Istologia Patologica-Policlinico Sant’Orsola
Malpighi, Bologna, Italy.
Oncocytic tumors are characterized by cells with aberrant mitochondrial
hyperplasia . Somatic mutations in mitochondrial genome (mtDNA)
affecting respiratory chain complex I subunits have been previously
reported in this type of neoplasia. We report the first case of inherited
frameshift complex I mutation in the ND5 gene associated with a specific
tumor phenotype.
The mtDNA was sequenced in microdissected areas from an oncocytic
nasopharynx tumor and in different non-neoplastic tissues from
the patient and two of his siblings in order to confirm inheritance of
the mutation . Immunohistochemical analysis for complex I subunits
was performed on tumor tissue to study protein expression and results
confirmed by western blot. Quantification of the mutation load
in mitochondria and of the total mtDNA copy number in the tissues
analyzed for the patient and his siblings was performed . The oncocytoma
harbors a frameshift homoplasmic (all mtDNA copies mutated)
ND5 mutation which correlated with lack of expression of another mitochondrially
coded complex I subunit (ND6) . Conversely, oncocytic
cells expressing ND6 show heteroplasmy for the ND5 mutation and a
de novo homoplasmic pathogenic ND1 mutation . Such cells also present
a lower degree of mitochondrial hyperplasia as shown by mtDNA
copy number . The ND5 mutation is heteroplasmic in all normal tissues
of the patient and his siblings indicating a shift to homoplasmy only in
the tumor .
Since shift to homoplasmy of ND1and ND5 mutations occurs exclusively
in tumor cells, we conclude that complex I mutations may have
a selective advantage and accompany oncocytic transformation .
P04.175
Functional gene polymorphisms of 16 factors that influence risk
for oral cancer: A multivariate regression analysis of their effect
C. Yapijakis1 , Z. Serefoglou1 , D. Avgoustidis1 , A. Vylliotis1 , E. Critselis1 , S.
Spyridonidou1 , E. Nkenke2 , F. W. Neukam2 , E. Patsouris1 , E. Patsouris1 , E.
Vairaktaris1 ;
1 2 University of Athens Medical School, Athens, Greece, University of Erlangen
Medical School, Erlangen, Germany.
Introduction: Functional DNA polymorphisms in genes of factors related
to angiogenesis, inflammation and thrombosis have been associated
with increased predisposition for oral squamous cell carcinoma
(OSCC) by genetic association studies performed by our group and
others . This study examined the possible combinatory effect of 16
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