2008 Barcelona - European Society of Human Genetics

Cancer genetics
203G>A among patients with sporadic breast and ovarian cancer,
patients with the same types of cancer with BRCA1 mutations and a
control sample . It was shown that genotype E1038E-N372N-203AA
was associated with ovarian cancer risk for both sporadic and BRCA1associated
ovarian cancer (OR=6,8; P=0,04) . At the same time, genotypes
E1038E-N372H-203GA and G1038G-N372N-203GA were associated
with decreased ovarian cancer risk (OR=0,2; 0,1; P=0,04;
0,02, respectively) . In the sample of sporadic breast cancer genotype
E1038E-203GA was associated with decreased risk independently on
N372H genotypes (OR=0,1; P=0,0001) and G1038G-N372N - independently
on 203G>A (OR=0,2; P=0,01) . The sporadic breast cancer
risk was increased under E1038G-N372H (OR=2,1;P=0,04) . There
was no difference of any genotype frequencies and their combinations
between BRCA1 mutation carriers with breast cancer and control
sample. This may means that no risk modifications are required for
breast cancer localization under BRCA1 mutations . Thus the genotype
combination increasing cancer risk is different for ovarian and sporadic
breast cancer and those decreasing cancer risk are the same but degenerated
on N372H under breast cancer . The results demonstrate
that different genotype combination on the same SNPs may have
influence on modificating cancer risk of definite localization. The risk
genotypes on several SNPs may include both hetorozygotes and homozygotes
as on rare so on frequent alleles . It is necessary take into
account under polygene influence analysis.
P04.060
molecular cytogenetic analysis of malignant ovarian tumours
R. Mihalova 1 , P. Lnenicka 1 , N. Jancarkova 2 , M. Vrbova 1 , M. Janashia 1 , M. Krkavcova
1 , M. Kohoutova 1 ;
1 Institute of Biology and Medical Genetics of the 1st Faculty of Medicine and
General Teaching Hospital, Charles University, Prague, Czech Republic, 2 Department
of Gynaecology and Obstetrics of the 1st Faculty of Medicine and
General Teaching Hospital, Charles University, Prague, Czech Republic.
Ovarian cancer represents almost 30 % of the malignancies of the female
genital tract with the highest mortality of all of the gynaecological
cancers . Unfortunately, majority of patients is diagnosed at advance
stage of the disease . The genetic changes involved in pathogenesis
of ovarian cancer are still not completely understood . Currently
there are no specific prognostic markers for prediction of the disease
course, for earlier diagnostics or for individual therapeutic strategies .
One of possible biological markers of great importance are chromosome
changes . Chromosome aberrations in ovarian tumour cells are
highly complex with hypodiploid or polyploid constitution . The aim of
the study is to determine significant chromosome changes as reliable
predictive markers .
We examined 30 ovarian cancer samples by comparative genomic hybridization
. Chromosome imbalances were detected in 90 % of tumour
samples . The most frequent recurrent changes were gains of 1q, 3q,
8q and 20q and losses of 4p, 4q, 18p, 18q, 19q and 22q . The results of
molecular cytogenetic analysis were correlated with histological/morphological
and clinical findings. Summarized data showed that significance
of chromosome changes in our patients is relatively low . Despite
of these results particular chromosome regions were assumed to be
involved in ovarian cancerogenesis . These regions are worthy of further
investigations considering the presence of candidate genes .
Supported by grant MSM 0021620808 .
P04.061
Aberrant promoter methylation of GPR 0, ITGA and HOXD
in ovarian cancers induced by PRTFDC silencing
A. Kondo1 , L. Cai1,2 , M. Abe2 , Y. Morita1 , H. Yokoyama1 , S. Izumi1 , T. Ushijima2 ;
1 2 Tokai University, Isehara, Japan, National Cancer Center Research Institute,
Tokyo, Japan.
It is known that methylated CpG island (CGIs) in promoter region
could be seen in tumor-suppressor genes and disease markers . In
this study, we performed a genome-wide screening for altered methylated
DNA fragments with methylation-sensitive-representational difference
analysis (MS-RDA) to show aberrant promoter methylation of
CpG island in human ovarian cancers . We have obtained 185 DNA
fragments specifically methylated in an ovarian cancer cell line (ES-
2) . We used a normal human ovarian epithelial cell line, HOSE6-3
as a control . In this control cell line, 33 DNA fragments were derived
from putative promoter CGIs . Ten ovarian cancer cell lines were ana-
lyzed by methylation-specific PCR, and seven (GPR150, LOC222171,
PRTFDC1, LOC339210, ITGA8, C9orf64 and HOXD11) of the 33 CGIs
were methylated in one or more of the cell lines . Expression of down
stream genes of those methylated CGIs were analyzed by quantitative
reverse-transcription-PCR and the result showed that those genes
were not expressed in cell lines without unmethylated DNA . Demethylation
of methylated cell lines with 5-aza-2’-deoxycytidine restored
expression of two genes (PRTFDC1 and C9orf64) . In primary ovarian
cancers, CGIs of GPR150 (in 4 of 15 cancers), ITGA8 (2/15),
PRTFDC1 (1/15), and HOXD11 (1/15) were methylated. Silencing of
PRTFDC1 was revealed that aberrant methylation of GPR150, ITGA8
and HOXD11 could be candidate as tumor markers .
P04.062
the study of P53 gene nutations in patients of breast cancer in
Rafsanjan city
M. Mirzaei Abbasabadi, M. Hajizadeh, M. Mirzaee Abbasabadi, M. Mahmudi,
G. Asadi karam, E. Rezazadeh, M. Asiabanan;
Medical University of Rafsanjan, Rafsanjan, Islamic Republic of Iran.
Background: P53 gene Mutation is the most common genetic change
in human neoplasia . In breast Cancer, p53 mutation is associated with
more aggressive disease and worse overall survival . The PCR-SSCP
is the common test for mutation analysis of p53 .
Materials and methods: DNA extraction from 48 paraffin Tissue samples
of patients done by standard Phenol chloroform method, exons
5-8 amplified by PCR and PCR products underwent SSCP gel analysis
for detection of probable mutations .
Results: Abnormal movement of PCR products band in SSCP gel that
stained with silver nitrate reported as mutation . We found three mutations
in exon 5, 2 in exon 6, one in exon 7 and 2 in exon8 .
Discussion: Detection of P53 gene mutations can be helpful in pre
diagnosis and prevention of breast cancer and so in treatment . These
mutations occur in normal or benign breast tissue but resolutions of
this role in the pathogenesis or breast cancer will require long-term
follow-up studies .
P04.063
p53, p63 and p73 isoforms in breast cancer
Z. Milicevic 1 , V. Bajic 2 , B. Potparevic-Spremo 3 , L. Zivkovic 3 ;
1 “VINCA” Institute of Nuclear Sciences, Laboratory for Molecular Biology and
Endocrinology, Belgrade, Serbia, 2 Institute of Biomedical Research Galenika,
Belgrade, Serbia, 3 Faculty of Pharmacy, Institute of Physiology, Department of
Biology and Human genetics, Belgrade, Serbia.
The spectrum of genetic alterations identified in cancer cells includes
mutations in various genes leading to structural and functional dysfunctions
in signal transmission as well es over-or under expression
of positive or negative signal generating proteins . Recently, two family
members of the suppressor gene p53 have been described, p63 and
p73, which seem to be necessary for specific p53-induced stress-response
pathways .
Furthermore, p63 and p73 appears to be crucial to determine the cellular
sensitivity to anticancer drugs, particularly in tumors lacking functional
p53 .
For analysis we used invasive breast carcinoma of common types
with a different differentiation and stages as well as a normal brest
tissue from patients with benign and malignant tumors . Protein p53expression
was estimated by Western blot analysis using anti p53 Abs
DO-7 and CM-1 . Our data show that brest cancer cells express nine
different isoforms of p53, p63 and p73 . The changes in the interactions
between p53,p63 and p73 isoforms are likely to be fundamental to our
understanding in the transition between normal cell cycling and the
onset of tumor formation .
Therefore, determination of p53 status in clinical studies is much more
complex than hitherto appreciated . It suggests that it requires an integrated
and complex analysis of p53 isoform expressions associated
with p53 mutation analysis and immunohistichemistry . To date, no clinical
studies have integrated all those p53 parameters to determine p53
status .
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