European Human Genetics Conference 2007 June 16 – 19, 2007 ...

Cancer genetics
Penetrance of PTEN mutations was high and expressions were
Cowden syndrome stigmata in early infancy or childhood and cancer
in adolescence or early adulthood. All families but one were small, and
de novo mutations were found. Outside clinically identifiable Cowden
families, PTEN mutations may not contribute to inherited breast cancer.
P0611. Analysis of TP53 Arg72Pro and MDM2 SNP309 T>G
polymorphisms as modifier factors in hereditary retinoblastoma.
K. Sampieri 1 , F. Ariani 1 , D. Giachino 2 , G. Mandrile 2 , M. De Marchi 2 , M. Bruttini 1 ,
M. Mencarelli 1 , F. Mari 1 , T. Hadjistilianou 3 , S. De Francesco 3 , A. Acquaviva 4 , A.
Renieri 1 ;
1 Medical Genetics, University of Siena, Siena, Italy, 2 Medical Genetics SSD,
ASO San Luigi Orbassano, Turin, Italy, 3 Retinoblastoma Referral Center, Department
of Ophtalmology, Siena, Italy, 4 Pediatrics Department, University of
Siena, Siena, Italy.
Retinoblastoma (RB) is the most common primary intraocular malignancy
in children, arising by two-hit inactivation of the RB1 gene.
Hyper-expression of negative p53 regulators was recently found as a
frequent somatic event. Most RB1 mutation carriers develop multifocal
RB. However, they show a broad range of phenotypic variability (age
of onset, involvement of one/two eyes and needed therapy). To test the
hypothesis that this may in part results from variable function of genes
involved in cell cycle and apoptosis, we investigated the effect of two
functional polymorphisms, one in TP53 (Arg72Pro) and the other in the
promoter of MDM2 (SNP309 T>G), on the age of tumour diagnosis.
The TP53 Pro allele has been shown to have a weaker proapoptotic
activity and to influence age of onset in Lynch syndrome; the MDM2
309G allele to accelerate tumour formation in Li-Fraumeni syndrome
and sporadic cancers. We tailored specific Pyrosequencing (C) assays
for the two SNPs and genotyped 43 RB patients with a characterized
or suspected RB1 germline mutation (i.e. familial and bilateral
cases). At univariate analysis, neither the MDM2 nor the TP53 SNP
did reveal significant differences on RB onset. We then evaluated their
combined effect through modelling estimates. Patients with the GG-
ProPro genotype showed an earlier tumour onset compared to those
with GG-ArgArg or GG-ArgPro. An increased number of patients is
needed to firmly establish this association. This approach could help in
better characterizing the role of the p53 pathway in RB carcinogenesis,
and defining more accurate prognosis for patients.
P0612. RNASEL gene polymorphisms and the risk of prostate
cancer: a meta-analysis
H. Li1 , B. Tai2 ;
1 2 National Cancer Centre Singapore, Singapore, Singapore, National University
of Singapore, Singapore, Singapore.
Studies revealing conflicting results of the role of RNASEL polymorphisms
Glu265X, Arg462Gln and Asp541Glu on prostate cancer risk
led us to perform a meta-analysis on published data investigating the
association of these polymorphisms and the prostate cancer risk.
We performed a meta-analysis of 5 studies with Glu265X genotyping,
7 studies with Arg462Gln genotyping and 6 studies with Asp541Glu
genotyping. The overall results of the meta-analysis suggested no major
influence of these variants on the prostate cancer risk. However,
analysis of the Asp541Glu polymorphism by ethnicity showed that
the genotypes with Glu variant including Asp/Glu (Familial cases vs.
Control: OR=1.38, 95% CI=1.04 - 1.82; Sporadic cases vs. Control:
OR=1.26, 95% CI=1.07 - 1.48; Prostate cancer vs. Control: OR=1.29,
95% CI=1.12 - 1.48) and Asp/Glu+Glu/Glu (Familial cases vs. Control:
OR=1.37, 95% CI=1.10 - 1.70; Sporadic cases vs. Control: OR=1.24,
95% CI=1.07 - 1.44; Prostate cancer vs. Control: OR=1.27, 95%
CI=1.13 - 1.44) increased the prostate cancer risk in Caucasians, thus
suggesting a dominant model for the Glu variant. Analyses by subpopulation
also showed no evidence of effects of either Arg462Gln or
Glu265X on the prostate cancer risk in Caucasians.
Our meta-analysis of available studies indicates that as compared with
genotype Asp/Asp, the Glu variant at the Asp541Glu polymorphism increases
the risk of prostate cancer by no more than 2-fold in Caucasian
subjects, regardless of family history of the disease. This suggests that
genuine genetic effects of this polymorphism probably account for only
a small part of prostate cancer in the Caucasian population.
1 0
P0613. Chracterization of chromosomal alterations in paraffinembedded
salivary gland tumors by comparative genomic
hybridization.
G. Floridia 1 , F. Censi 1 , M. Foschini 2 , V. Falbo 1 , D. Taruscio 1 ;
1 Dipartimento di Biologia cellulare e Neuroscienze, Istituto Superiore di Sanità ,
Roma, Italy, 2 Section of Pathology, University of Bologna, Bellaria Hospital,
Bologna, Italy.
Salivary gland tumours (SGTs) are rare tumors of the neck and head
with an overall incidence in the Western world of approximately 2.5-
3/100.000/year. SGTs involve the major glands (parotid, submandibular
and sublingual) and the minor glands (oral mucosa, palate, uvula,
floor of mouth, posterior tongue, retromolar area and peritonsilla area,
larynx and paranasal sinuses).
SGTs are remarkable for their histopathologic and biologic diversity;
they include benign and malignant tumors of epithelial, mesenchymal
and lymphoid origin.
Although exposure to ionizing radiation has been implicated as a cause
of SGTs, the etiology of most of these tumors cannot be determined;
moreover it’s difficult to determine the prognosis and select the optimal
therapeutic modality. The study of molecular pathogenesis of SGTs is
a challenging task because of the rarity and histopathological diversity
of these malignancies.
Comparative Genomic Hybridization (CGH) is a powerful tool for detecting
chromosomal aberrations in archival paraffin embedded tumor
samples.
CGH analysis, performed on four adenoid cystic tumor samples (with
different hystotypes) and one pleomorphic adenocarcinoma , revealed
fourteen aberrations (on average 2.8 per case). Gains involved chromosomal
regions 3q28-29, 4q35, 6q27, 10q15, 18p11, 20p13,22q12-
13; losses involved 2q36 -q37, 6p25, 11p15, 22q13. The correlation
of CGH results with clinical-pathological data and a comparison with
literature data will be discussed.
This work has been funded in the frame of “Programma di collaborazione
ISS-NIH , Area Malattie Rare” Fasc.526/B
P0614. Gene copy number profiling mucoepidermoid
carcinomas of salivary glands by using array comparative
genomic hybridization
K. Jee 1 , K. Heikinheimo 2 , S. Knuutila 1 , I. Leivo 1 ;
1 Haartmanin Institute, Helsinki, Finland, 2 Institute of Dentistry, Turku, Finland.
The recent development of DNA microarray- based comparative genomic
hybridization has greatly facilitated the identification of chromosomal
regions of imbalance and the target genes in them. The purpose
of this paper is to identify whole genome aberrations in mucoepidermoid
carcinoma (MEC) of salivary gland and to corelate genetic differences
and histologic in mucoepidermoid carcinomas. We performed
an oligonucleotide based array-comparative genomic hybridization
(aCGH) survey in 9 cases of low-and 5 cases of high-grade mucoepidermoide
carcinomas. All cases of low-grade MECs had no genomic
aberrations while in high-grade MECs were seen a complex for copy
number aberrations including 3q amplification.
In conclusion, by using aCGH, we defined differences of copy number
aberrations between the histologic grades of the MECs that might be a
directly influence to the behavior of these tumors.
P0615. SEMA B is a candidate tumor suppressor gene on
19p13.3
V. V. Strelnikov 1,2 , E. B. Kuznetsova 1,2 , E. A. Pudova 3 , S. S. Larin 4 , M. V.
Nemtsova 1,2 , D. V. Zaletayev 1,2 ;
1 Moscow Medical Academy, Moscow, Russian Federation, 2 Research Centre
for Medical Genetics, Moscow, Russian Federation, 3 Russian State Medical
University, Moscow, Russian Federation, 4 Institute of Gene Biology, Moscow,
Russian Federation.
It was previously suggested, by the results of high-resolution 19p13.2-
13.3 allelotyping in breast carcinomas, that this region might contain
at least four tumor suppressor genes corresponding to the peak frequencies
of loss of heterozygosity (LOH). We have recently found
one of the 19p13.3 genes, SEMA6B, to be abnormally methylated in
breast cancer. The SEMA6B promoter CpG island was methylated
in 37/98 (38%) tumors and in 3/98 (3%) adjacent apparently normal
tissue samples (p