2008 Barcelona - European Society of Human Genetics

Cancer genetics
way consists of three major components: the nuclear core complex
composed of at least eight FA proteins (group 1), which activates the
“group 2” proteins FANCD2 and FANCI (ID complex) . The ID complex
is then targeted to chromatin and co-localizes with “effector” proteins
such as BRCA2 or RAD51 (group 3) . Recent progress in understanding
the FA/BRCA network was achieved by the discoveries of the three
FA genes FANCI, FANCJ and FANCN . Besides FANCD2, FANCI is
the second monoubiquitinated member of the FA/BRCA pathway . We
show the biallelic mutations of four FA-I patients . The 5`-3`helicase
BRIP1 and the BRCA2-binding protein PALB2 both act downstream
of the monoubiquitination step and belong to the “group 3” proteins .
We identified biallelic truncating BRIP1 mutations in eleven FA patients
. In an additional seven FA patients we found biallelic PALB2
mutations, designating PALB2 as FANCN . Interestingly, investigations
of FANCJ and FANCN have shown that all known group 3 proteins
(BRCA2/FANCD1, BRIP1/FANCJ, PALB2/FANCN) are breast cancer
susceptibility genes . This recent emergence of new FA genes not only
facilitated further understanding of a major DNA repair pathway, but
also makes connections to tumorigenesis and cellular aging (Neveling
et al ., Z Gerontol Geriatr 2007) .
P04.145
Role of Helicobacter Pylori in gastric adenocarcinoma : special
emphasis on gender, androgen receptor and angiogenic factors
S. Arbabi Bidgoli 1 , M. Djamali Zavarhei 2 , M. Soleimani 1 , S. Sajadi 1 ;
1 Faculty of Pharmacy,Isalmic Azad University(IAU), Tehran, Islamic Republic of
Iran, 2 Department of Pathology,College of Medicine,Tehran University of Medical
Sciences, Tehran, Islamic Republic of Iran.
H. pylori increase the risk of gastric cancer which has higher incidence
in men globally . Due to animal studies male gastric tissues respond
more rapidly to H . pylori but the underlying roles of sex hormones and
angiogenic factors remained unclear in both genders . We studied the
roles of H pylori on tissue levels of Androgen Receptor (AR), uPA,
MMP9 and TP as three major angiogenic and prognostic markers in
gastric cancer . Malignant and non malignant tissues of 72 gastric adenocarcinoma
cases who underwent surgery from 2004-2007 were
analyzed by immunohistochemical methods . Higher prevalence of H
pylori in males, lack of AR expression in normal cells of females and
lower expression of AR in tumoral cells of females (p=0 .03) were the
first significant differences between two genders. H pylori infection was
evaluated as a relative risk factor of AR expression in males (OR=5)
and females (OR=3) that means most of AR (+) tumors had history of
H .pylori infection in their normal cells . Although females showed higher
uPA expression (p=0 .007) but H pylori negative tumors showed higher
risk of tumoral uPA (OR=1 .13), MMP9 (OR=1 .24) and TP expression
(OR=1 .12) in males . By recording the strong role of AR and h pylori
infection on the expression of tumoral uPA and other angiogenic factors
in women (OR=11 ) we concluded that H pylori plays inconsistent
roles in two genders by inducing different unknown genes but AR plays
similar roles in both genders by increasing the tissue levels of angiogenic
factors .
P04.146
High frequency of mLH1 and msH2 mutations among familial
gastric cancer patients
A. S. Tsukanov1 , A. N. Loginova1 , N. I. Pospekhova1 , T. A. Muzaffarova1 , L. N.
Lubchenko2 , M. P. Nikulin2 , A. V. Karpukhin1 ;
1 2 Research Centre For Medical Genetics, Moskow, Russian Federation, Cancer
Research Centre, Moskow, Russian Federation.
Mutations of CDH1 gene are associated with familial diffuse gastric
cancer . MLH1 and MSH2 mutations are associated generally with hereditary
non-polyposis colon cancer syndrome that may include gastric
cancer . So MLH1 and MSH2 mutations predispose to gastric cancer .
However a frequency of MLH1 and MSH2 mutations among patients
with familial gastric cancer unselected on cancer type or familial history
is unknown .
We investigated the sample of 30 patients with familial gastric cancer
on mutations of CDH1, MLH1 and MSH2 genes . The structure of our
sample was near to a distribution of different familial gastric cancer
types in the population and includes 8 families with diffuse gastric
cancer . There were 5 germline MLH1 and MSH2 mutations among 30
patients (16,6%) . Mutations have been found in families with gastric
cancer only as well as in the families with both gastric and colon can-
cer cases . There were no mutations in CDH1 gene . Thus, a frequency
of MLH1/MSH2 mutations associated with familial gastric cancer is
higher in comparison with the CDH1 gene mutations (P=0,026) .
P04.147
telomere function in giant cell tumors of bone
S. Gebre-Medhin1 , Y. Jin1 , T. Jonson1 , K. Broberg2 , N. Mandahl1 , F. Mertens1 ;
1 2 Department of clinical genetics, University hospital, Lund, Sweden, Department
of occupational medicine, University hospital, Lund, Sweden.
BACKGROUND: Giant cell tumor of bone (GCT) is a locally aggressive
tumor accounting for 1/20 of all bone tumors . Morphologically, GCTs
show osteoclast-like giant cells mixed with mononuclear putative neoplastic
cells . Cytogenetically, GCTs often show telomeric associations
(tas) paralleled by an otherwise normal karyotype . It remains to be
established whether tas in GCT represent deregulation of cis-regulatory
or trans-regulatory mechanisms at the telomere, or a combination
thereof, or are caused by other yet unknown mechanisms .
METHODS: DNA was extracted from fresh frozen biopsies of 20 GCTs
for telomere length analysis . From the same 20 cases, RNA was extracted
for quantitative RT-PCR analysis concerning the expression
levels of four genes (TERT, TRF1, TRF2 and POT1) involved in telomere
function . FISH analysis was performed to evaluate the frequency
of telomere-negative chromosome ends .
RESULTS: No correlation between presence of clonal chromosome
aberrations and telomere length in tumor cells could be detected . At
FISH analysis there was a correlation between frequency of tas and
number of telomere-negative chromosome ends . Expression of TERT,
TRF1, TRF2 and POT1 was found in all tumors . Analysis regarding the
correlation between expression levels of individual genes and cytogenetic
and clinical features is ongoing .
CONCLUSION: In view of our preliminary data, it is unlikely that the
high frequency of tas could be explained by altered expression levels
of any of the investigated genes . However, it can not be ruled out that
altered function at the protein level of TERT, TRF1, TRF2 or POT1 is
involved in tas formation .
P04.148
Overexpression of wild-type p53 suppresses Cathepsin B
(CSTB) in glioblastoma cells
M. Heidari, M. Safari, O. Seyedi;
Tehran University/Medical Sciences, Tehran, Islamic Republic of Iran.
The tumor suppressor protein p53 plays critical role in modulating cellular
functions such as cell cycle arrest and apoptosis . Due to its function
in growth inhibition as well as contribution of its mutated form in >50%
of human tumors particularly a significant proportion of glioma cases,
p53 is considered a fundamental tumour suppressor gene . In order to
investigate potential p53 target gene(s), we employed overexpression
of wild-type p53 via recombinant adenovirus (Ad-GFP-P53) which encodes
green fluorescent protein and p53 separately, and cDNA AFLP
approaches in U87 glioblastoma cells . In response to overexpression
of wild-type p53, cDNA AFLP results revealed the suppression of cathepsin
B (CSTB) gene which encodes a protease but not in infected
cells with Ad-GFP which does not express p53 and mock control .
Semi-quantitative RT-PCR analysis confirmed the activation of CTSB
gene in cells containing Ad-GFP and mock control however; its transcriptional
activity was suppressed in infected cells with Ad-GFP-P53 .
In addition, computational analysis detected several potential p53 DNA
target sequences within introns of CTSB genes . Taken together our
results suggested that CTSB gene might be directly regulated by p53
protein as a transcription regulatory protein in glioblastoma .
P04.149
mGmt and p15 promotor methylation - prognostic parameters
for TMZ chemotherapy response?
S. Wemmert 1 , R. Ketter 1 , M. Bettscheider 1 , S. Alt 2 , K. Kammers 3 , J. Rahnenführer
3 , W. Steudel 1 , S. Urbschat 1 ;
1 Department of Neurosurgery, Saarland University, Homburg, Germany, 2 Institute
of Immunology, National Public Health Laboratory, Luxembourg, Luxembourg,
3 Department of Statistics, Technical University Dortmund, Dortmund,
Germany.
Glioblastomas are the most frequent and malignant brain tumors in
adults . Surgical cure is virtually impossible and despite of radiation and
chemotherapy the clinical course is very poor . Epigenetic silencing of