2008 Barcelona - European Society of Human Genetics

Cancer genetics
P04.179
molecular genetic analysis of apparently sporadic
pheochromocytomas and paraganglioma in czech patients
Z. Musil 1 , J. Vesela 1 , A. Krepelova 1,2 , A. Panczak 1 , J. Widimsky 3 , T. Zelinka 3 , A.
Puchmajerova 2 , M. Simandlova 2 , Z. Frysak 4 , J. Vaclavik 4 , M. Kohoutova 1 ;
1 Institute of Biology and Medical Genetics of the First Faculty of Medicine,
Prague, Czech Republic, 2 Institute of Biology and Medical Genetics, 2nd Faculty
of Medicine and Teaching Hospital at Motol, Prague, Czech Republic, 3 3rd
Medical Department - Clinical Department of Endocrinology and Metabolism,
1st Faculty of Medicine, Prague, Czech Republic, 4 3rd Clinical Department,
Faculty of Medicine and Faculty Hospital, Palacky University, Olomouc, Czech
Republic.
Pheochromocytoma is a tumor arising in adrenal or extra-adrenal sites
and occurs as a sporadic form or, less frequently, in familial setting as
a part of inherited syndromes . Paraganglioma of the head and neck
occurs mostly sporadically and also in syndromic or non-syndromic
familial settings . To date, four susceptibility genes for pheochromocytoma
have been reported that included RET proto-oncogene, VHL tumor
suppressor gene, and recently identified genes SDHB and SDHD
for succinate dehydrogenase subunit B and D, respectively . Mutations
in these genes can predispose an individual to pheochromocytoma
and/or paraganglioma . All these genes were analyzed to investigate
possible genetic cause of pheochromocytoma and paraganglioma in
population of Czech patients . Among 147 patients two novel germline
(missense) mutations were found in the VHL gene . Further, one novel
coding single nucleotide polymorphism and one inversion, both in
SDHB gene, were detected . In one case of isolated pediatric onset of
neuroblastoma and paraganglioma we detected a novel splice site mutation
in SDHB gene . In addition, in one examined patient with paraganglioma
we detected mutation of the start codon in SDHD gene .
Supported by the grant project MSMT CR MSM0021620808
P04.180
carriers of germline c.1710+1355G>c substitution in the PML
gene are at an increased risk of gastrointestinal cancer
P. Plevova 1,2 , S. Walczyskova 1 , I. Jeziskova 1 , A. Krepelova 3 , K. Langova 4 , E.
Silhanova 1 ;
1 Department of Medical Genetics, Faculty Hospital, Ostrava, Czech Republic,
2 Medical Faculty, Palacky University, Olomouc, Czech Republic, 3 3. Institute of
Genetics, 2nd Medical Faculty, Charles University, Prague, Czech Republic,
4 Institute of Biophysics, Palacky University, Olomouc, Czech Republic.
Introduction: PML (promyelocytic leukemia) is a tumor suppressor gene .
We studied occurrence of c .1710+1355G>C (p .A570+232>P570+232)
substitution in alternatively spliced exon 7b of the PML gene in cancer
patients .
Patients and methods: Sporadic and hereditary breast, colon and
stomach cancer and multiple colon polyposis patients were included
into the study . The control group included 100 non-cancer patients .
The c .1710+1355G>C substitution was analyzed in genomic DNA using
restriction analysis . Its occurrence in each cancer versus control
groups was correlated using chí-square test.
Results: c .1710+1355G>C was found in 7 of 64 (11%) non-BRCA1/2
breast cancer (p=0,683), none of 24 BRCA1/2-associated breast
cancer (p=0,276), 15 of 57 (26%) non-HNPCC colon cancer or multiple
polyposis (p=0,003), none of 6 HNPCC-associated colon cancer
(p=0,988, chí-square test with Yates correction), 2 of 3 stomach cancer
patients (p=0,025, chí-square test with Yates correction) and 9 of 100
(9%) controls .
Conclusion: Our results suggest that germline carriers of the
c .1710+1355G>C substitution in alternatively spliced exon 7b of the
PML gene might be at an increased risk of gastrointestinal cancer or
polyposis .
Acknowledgements: The project was supported by IGA MZ CR
NR/9092-3/2006 .
P04.181
the 8q24 rs10505470 variant is not associated with prostate
cancer risk in patients from the Republic of macedonia
N. Matevska 1 , D. Petrovski 2 , S. Dzikova 2 , S. Banev 2 , V. Georgiev 2 , A. Sikole 2 ,
A. J. Dimovski 1 ;
1 Faculty of Pharmacy, Skopje, The former Yugoslav Republic of Macedonia,
2 Faculty of Medicine, Skopje, The former Yugoslav Republic of Macedonia.
Recent compelling evidence demonstrates chromosome 8q24 as
a prostate cancer (PC) susceptibility locus . Multiple variants within
three adjacent regions at 8q24 have been identified to impact the risk
of PC . Most commonly assessed variants are rs1447295 (region1),
rs16901979 (region2) and rs6983267 (region3) . Although regions 1
and 3 are close together, they are separated by a recombination hotspot
among individuals of European ancestry . Hence, all three neighboring
regions seem to contribute independently to the PC risk, and
the combined effects of SNPs across regions follow a multiplicative
model . In order to examine the association between the PC risk and all
three regions of 8q24 we designed a case-control study of randomly
selected PC patients and controls without history of any malignant disease
. Herein, we present the results of the association of PC risk and
rs10505470 variant which is known to be in strong LD with rs6983267
in region 3 . The rs10505470 genotypes were determined using custom
designed TaqMan SNP genotyping assay on a Real-time PCR
analyzer (MxPro 3005P) . We did not observe a difference in overall allelic
frequencies and genotype distribution {(A allele 0 .518 for patients;
0 .516 for controls); (AA 28 .24%, AG 47 .06%, GG 24 .71% for patients;
AA 27 .60%, AG 47 .92%, GG 24 .48% for controls)} . Furthermore there
was no significant difference after stratification of patients in subgroups
according to age and Gleason score. Our findings led us to conclude
that rs10505470 variant is not implicated with PC risk, time of onset or
PC aggressiveness in Macedonian population .
P04.182
Alpha-methylacyl-CoA racemase, a novel specific biomarker for
prostate cancer
R. O. Dumache 1 , B. G. Bumbacila 1 , A. Anghel 1 , F. Miclea 2 , M. Puiu 3 ;
1 ’Victor Babes’ University of Medicine and Pharmacy, Faculty of Medicine,
Biochemistry Department, Timisoara, Romania, 2 ’Victor Babes’ University of
Medicine and Pharmacy, Faculty of Medicine, Urology Department, Timisoara,
Romania, 3 ’Victor Babes’ University of Medicine and Pharmacy, Faculty of
Medicine, Medical Genetics Department, Timisoara, Romania.
Alpha-methylacyl-CoA racemase, abbreviated in data bases as AM-
ACR or P504S, is a 382 amino acid protein that plays a critical role in
peroxisomal and mitochondrial beta oxidation of branched chain fatty
acid and bile acid intermediates, dihydroxycholestanoic acid and trihydroxycholestanoic
acid, molecules. Specifically, it catalyses the conversion
of (R) α - methyl branched chain fatty acyl CoAs to their (S)
stereoisomers, because only stereoisomers with the 2-methyl group
in the (S) position can be metabolized by peroxisomal oxidases, the
first enzymes in the ß oxidation pathway . It is well known that the main
sources of branched chain fatty acids are the dairy products and red
meet pork and beef, the consumption of which has been associated
with an increased risk for prostate cancer in men, in multiple studies .
We evaluated the AMACR gene expression in 32 patients aged 55 to
80, with total PSA values in a range of 2 to 40 ng/ml . 26 patients were
diagnosed positive for prostate intraepithelial carcinoma and they had
PSA values greater than 11 ng/ml . In these 26 men, we found by using
PCR and micro array techniques on needle biopsies that they had
an over expressed gene for AMACR, too . The other 6 patients with
total PSA values smaller than 11 ng/ml, had normal expression of the
AMACR gene .
According to our results, we propose the use of AMACR as an important
marker of prostate cancer in Urology Clinics beside PSA and
morphopathological diagnostic .
P04.183
cAG repeat number in androgen receptor gene and prostate
cancer
S. Trivodalieva 1 , N. Matevska 2 , A. Dimovski 2 , G. D. Efremov 1 , D. Plaseska-
Karanfilska 1 ;
1 Macedonian Academy of Sciences and Arts, Research Centre for Genetic
Engineering and Biotechnology, Skopje, The former Yugoslav Republic of
Macedonia, 2 Faculty of Farmacy, Farmacogenetic laboratory, Skopje, The former
Yugoslav Republic of Macedonia.
Prostate cancer (PC) is the second leading cause of cancer deaths
among men . The effects of androgens on prostatic tissue are mediated
by the androgen receptor (AR) through the androgen receptorandrogen
complex . The 5’ end of exon 1 of the AR gene includes a
polymorphic CAG triplet repeat that varies in number between 10 to