2009 Vienna - European Society of Human Genetics

Cancer genetics
licular thyroid cancer (80-90%), which belong to group of tumors well
prognoses and slowly progress and benignity. Very serious problem
are recurrences and regional or remote metastasis. Progression from
well differentiated thyroid cancer to malignant anaplastic carcinoma
is possible also. In this focus, very important seems to be searching
for molecular markers of disease course, good or poor prognosis and
response on medical treatment as well. It is expected that polymorphisms
research in genes demonstrating association with neoplastic
diseases will be helpful in understanding of molecular mechanisms of
thyroid gland tumors development. The dependence of differential thyroid
cancer occurrence on DNA variation: I157T in CHEK2 gene, R72P
in P53 gene, 1007fs in NOD2/CARD15 gene and synonymic G2497T
substitution in RET protooncogene was examined. 296 patients with
differentiated thyroid cancer and 200 individuals from population group
was examined. We used pyrosequencing technique. There were no
significant differences in allele or genotype frequencies in analysis of
RET G2497T substitution and R72P in P53 gene but mutated allele
frequencies of 1007fs and I157T was 8,95% and 4,9% in patients with
thyroid cancer, compared with 2,92% and 2,1% in control individuals
respectively. Our findings indicates that particular characteristics of
cancer risk genes on RNA level as well as DNA changes is necessary.
Additionally a summary effect of different SNP changes as a cancer
predisposing factor is possible, so further analysis will be performed.
P06.032
two cases of double heterozygotes in families with hereditary
cancer
L. Foretova1 , M. Lukesova1 , J. Hazova1 , M. Navratilova1 , P. Plevova2 , E. Machackova1
;
1 2 Masaryk Memorial Cancer Institute, Brno, Czech Republic, University Hospital,
Ostrava, Czech Republic.
BRCA1 and BRCA2 genes are tested in all familial or sporadic early
onset breast and ovarian cases, which fulfil inclusion criteria. Two of
the CHEK2 gene mutations, c.1100delC and deletion of exon 9-10,
are also tested as a last step of examination, in all BRCA1/2 negative
probands. MLH1, MSH2 and MSH6 genes are tested in cases of possible
HNPCC syndrome. In one of our families both BRCA1 deletion
of exon 20 and CHEK2 c.1100delC was detected in a proband with
breast cancer at 44; her mother had breast cancer at 40 and ovarian
cancer at 48. Proband has three daughters, one non-carrier, one carrier
of CHEK2 mutation and one carrier of BRCA1 deletion. In other
family originally tested for Lynch syndrome, MLH1 mutation (splice
site) was detected in a proband with rectal cancer diagnosed at 58,
whose father and grandfather had stomach cancer. Because his sister
had breast cancer and mother had ovarian cancer, additional testing
was provided and a BRCA1 mutation (protein truncating) was discovered.
The occurrence of double heterozygotes is possible but probably
rare. The clinical geneticist should carefully evaluate family history and
indicate testing of additional hereditary cancer syndromes especially
in probands with positive cancer occurrence from both parents. The
preventive recommendations should be explained even in non-carriers
of high-risk familial mutation. Supported by the Ministry of Health of the
Czech Republic: Grant MZ0MZO2005
P06.033
Novel variants of fusion gene transcripts in soft-tissue
sarcomas.
T. V. Kekeeva1,2 , A. A. Ryazantseva1 , L. E. Zavalishina1 , Y. Y. Andreeva1 , G. A.
Frank1 ;
1Herzen Moscow Oncological Research Institute, Moscow, Russian Federation,
2Sechenov Moscow medical academy, Moscow, Russian Federation.
Soft-tissue sarcomas have specific recurrent chromosomal translocations
producing chimeric gene fusions, which regarded as a major
factor in the development of these tumors. Fusion of FUS and CHOP
gene is a common genetic event found in liposarcomas. Majority of
Ewing’s sarcomas are associated with fusion gene EWS-FIi1. These
specific translocations can be used for exact diagnosis in poorly differentiated
tumors.
We examined 28 formalin-fixed paraffin-embedded sarcoma samples
(20 liposarcomas, 8 Ewing’s tumors). Translocations were tested by
FISH, characterization of fusion genes FUS/CHOP, EWS/FLI1 was
performed by RT-PCR and sequencing.
We observed translocations in 18/20 cases of liposarcomas and in
8/9 cases of Ewing’s tumors. In 19/25 cases endogenous control B2M
indicated adequate RNA quality. We found EWS/FLI1 fusion genes in
3/8 Ewing’s sarcomas. In 2 cases ews exon 7 being fused to fli1 exon
6, in 1 case ews exon 7 being juxtaposed to 10 ews exon following by
fli1 exon 6 (novel fusion variant).
We detected FUS/CHOP fusion gene in 45% (5/11). All cases had a
type fusion transcript involving fusion of FUS exon 5 with CHOP exon
2. Two novel transcript modifications were found, of which one had 6
nucleotides insertion and the other lacked 14 nucleotides of CHOP.
Moreover we found two different variants of the transcript in one sample,
caused by alternative splicing apparently.
Further investigation of structural attributes of fusion genes may be
helpful for the prospective target therapy of patients with such fusion
oncogenes and give insight into the malignant sarcoma development.
P06.034
Different genetic reasons of gastric cancer
A. Tsukanov1 , A. Loginova1 , N. I. Pospekhova1 , T. A. Muzaffarova1 , L. N. Lubchenko2
, M. P. Nikulin2 , E. K. Ginter1 , A. V. Karpukhin1 ;
1 2 Research Centre For Medical Genetics, Moscow, Russian Federation, Cancer
Research Centre, Moscow, Russian Federation.
Mutations of CDH1 gene are associated with familial diffuse gastric
cancer in some populations. MLH1 and MSH2 mutations also may predispose
to gastric cancer.
Three samples of patients for mutations and SNPs in the CDH1, MLH1
and MSH2 genes were studied: 30 patients with familial gastric cancer,
99 patients with sporadic gastric cancer and a control sample of 112
probands by SSCP and sequencing.
Mutations in gene CDH1 have not been found. We investigated our
sample of familial gastric cancer and found 5 germline MLH1 and
MSH2 mutations (16,6%). We have studied the significance of the
CDH1 -160C/A variant in a promoter region for familial and sporadic
forms of gastric cancer. The association of homozygote variant -160A/
A with gastric cancer was shown for patients as with familial (OR=12,3;
p=0,03) so sporadic form (OR=8,4; p=0,02). In addition it has been
shown that the genotype 2076TT is associated with risk of a gastric
cancer in a presence of a genotype -160CA for sporadic (OR=9,8;
p=0,002) and the familial form (OR=12,3, p=0,009) but does not lead
to the risk increasing in a presence of -160CC genotype. It is interesting
that -160AC/2076TT genotype have not been found among 112
healthy controls.
In summary, mutations increasing cancer risk have been shown
more frequent in MLH1 and MSH2 genes than CDH1. The genotype
-160AC/2076TT of CDH1 has been certain for the first time as a risk
genotype of gastric cancer.
P06.035
cDH1-160 polymorphism in Gastric cancer; could be an
informative marker?
A. Falahati 1 , M. Khoshsoror 1 , M. Karimpour 2 , Z. Soltani 2 , F. Jokar 1 , M. Jamali 1 ,
R. Shahrokhi Rad 1 , F. Rezaei 1 , M. Fallah 1,3 , F. Mansour-Ghanaei 1 , A. Ebrahimi 3 ;
1 Gastrointestinal and Liver Diseases Research Center, Guilan University of
Medical Sciences, Rasht, Islamic Republic of Iran, 2 Pasteure Institute, Tehran,
Islamic Republic of Iran, 3 National Institute for Genetic Engineering and Biotechnology
(NIGEB), Tehran, Islamic Republic of Iran.
Introduction: Despite declining incidence rates, gastric cancer (GC) is
a major cause of death worldwide and in Guilan Province, I.R. Iran.
E-Cadherin is an adhesion molecule that is thought to be involved in
gastric cancer patients. Polymorphism at position −160 C/A has been
shown to affect GC risk in some studies.
Material and methods: DNA was extracted from peripheral blood cells
according to the protocols. E-Cadherin polymorphism at position -160
C/A was investigated using PCR RFLP method.
Result: Fifty-two cases (17 gastric cancer and 35 of their healthy 1st
relatives) were included in the study. Allele Frequency was 90.4 % for
C and 9.6 % for A. 84.6 % of cases were Homozygote (CC in 43 cases
and AA in 1 case) and 15.4 % were Heterozygotes (C/A in 8 cases).
A>C polymorphism was seen in 17.3 % of cases (in homozygote or
heterozygote state). This have seen in 23.5 % of those with gastric
cancer and in 14.3 %.of healthy one with gastric cancer in their 1 st
relatives
Conclusion: Polymorphisms in CDH1 have inconsistent relation
with gastric cancer studies. In the present study, the CDH1−160C/A