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

Cancer genetics
the detection in 4 cases of different 3q abnormalities not previously
found by conventional cytogenetics. FISH analysis with BAC clones
was found to be a useful tool to identify the chromosome breakpoints
affecting EVI1 locus in patients with 3q26 rearrangements.
P0547. Clinical and genetic characterization of Austrian FAP
patients - A first report
B. Wolf 1 , S. Gruber 1 , E. Roth 1 , J. Karner-Hanusch 2 ;
1 Medical University of Vienna, Department of Surgery, Research Laboratories,
Vienna, Austria, 2 Medical University of Vienna, Department of Surgery, Vienna,
Austria.
Background: Familial adenomatous polyposis (FAP) is an inherited
colorectal cancer syndrome characterized by the early onset of numerous
polyps and associated with germ-line mutations in the adenomatous
polyposis coli (APC) gene.
Material and Methods: We analyzed a series of 128 unrelated Austrian
families clinically diagnosed with FAP for mutations in the APC gene.
Protein-truncation test and heteroduplex analysis were used as prescreening
tests previous to DNA sequence analysis. Linkage analysis
was performed with 4 polymorphic microsatellite markers.
Results and Conclusion: Medical examination revealed 69 (67.6%)
patients with classical FAP symptoms and 33 (32.4%) patients with an
attenuated or atypical phenotype. In 55.6% of the families a genetic
defect was identified with at least one of the methods applied. The
detection of a genetic defect in the APC gene was highly significantly
associated with a classical phenotype, the detection of innumerable
polyps, lesions of the retinal pigment epithelium (CHRPE) and desmoids.
DNA sequence analysis identified 61 pathogenic APC mutations.
Six mutations were detected in more than one family. Twentynine
mutations are novel. Only a polymorphic fragment pattern could
be associated with the inheritance of the disease in two families. This
study is the first comprehensive report of APC gene mutations in Austrian
FAP patients.
P0548. Association of biallelic BRCA2 mutations in a child with
rhabdomyosarcoma
V. Nicolas 1 , A. Defachelles 2 , B. Catteau 3 , J. Peyrat 4 , S. Lejeune-Dumoulin 1 , S.
Manouvrier-Hanu 1 , M. Holder-Espinasse 1 ;
1 Service de Génétique Clinique, Hôpital Jeanne de Flandre, Lille, France, 2 Service
d’Oncologie Pédiatrique, Centre Oscar Lambret, Lille, France, 3 Service de
Dermatologie, Hôpital Jeanne de Flandre, Lille, France, 4 Biologie Moléculaire,
Centre Oscar Lambret, Lille, France.
Growth retardation, microcephaly and solid tumour in childhood can
be linked to Fanconi anaemia. Fanconi anaemia is an autosomal recessive
heterogeneous condition, consisting in 11 complementation
groups and involving at least twelve genes. Recently, biallelic mutations
in BRCA2 have been discovered in patients classified as Fanconi
anaemia complementation group FA-D1.
We report on a further case presenting with rhabdomyosarcoma, intrauterine
and postnatal growth retardation and microcephaly. This is
the first child of non consanguineous parents. At the age of one year,
cutaneous lesions were observed (naevi, haemangioma and cutis
marmorata). The motor milestones were achieved normally. Karyotype
was 46XX, but breakage studies were not performed.
At 1.5 year of age, an embryonic paravertebral rhabdomyosarcoma
with vertebral extension and pulmonary metastasis was detected. The
association of this solid tumour and the growth retardation was suggestive
of Fanconi anaemia type FA-D1, despite no other typical features
of this condition were observed.
Sequencing of BRCA2 revealed two deletions: one in exon 8 (886del-
GT) and the other in exon 22 (9132delC). These two mutations are
deleterious and have been previously reported in either Fanconi anaemia
or breast cancer.
Heterozygous BRCA2 mutation carriers are at risk of breast and other
cancers. In the family pedigree, there were cases of breast cancer in
the father’s family and cases of prostate and pancreatic cancer in the
mother’s family. BRCA2 molecular analysis is pending in the parents.
We discuss the clinical phenotype of this rare form of Fanconi anaemia,
and the complexity of the management in these cases.
P0549. APC and MYH mutations in Czech and Slovak FAP
families
M. Šulová 1 , J. Štekrová 1 , K. Zídková 1 , Z. Kleibl 2 , V. Kebrdlová 1 , K. Veselá 1 , M.
Kohoutová 1 ;
1 Institute of Biology and Medical Genetics of the First Faculty of Medicine and
General Teaching Hospital, Prague, Czech Republic, 2 Institute of Biochemistry
and Experimental Oncology of the First Faculty of Medicine, Prague, Czech
Republic.
Germline mutations in the adenomatous polyposis gene (APC) result
in familial adenomatous polyposis (FAP) as well as an attenuated form
of this syndrome. FAP is an autosomal dominantly inherited disorder
predisposing to colorectal cancer.
We analyzed the APC gene for germline mutations in 59 Czech and
15 Slovak FAP patients. In addition, 50 APC-mutation-negative Czech
probands and 3 probands of Slovak origin were screened for large
deletions of the APC gene. Mutation screening was performed using
denaturing gradient gel electrophoresis and/or protein truncation test.
DNA fragments showing an aberrant electrophoretic banding pattern
were sequenced. Screening for large deletions was performed by multiplex
ligation dependent probe amplification (MLPA).
We identified 46 germline mutations among the 74 unrelated probands
including large deletions. We reported 20 novel germline APC mutations
and 3 large deletions encompassing the whole-gene deletions
and/or exon 14 deletion.
Some of the APC negative FAP/AFAP cases have recently been found
to be attributable to MYH associated polyposis (MAP), an autosomal
recessive syndrome caused by mutation in the MYH gene.
We screened for germline MYH mutations in 120 APC-mutation-negative
probands with classical and attenuated FAP. As a prescreening
to detect DNA sequence changes, denaturing high performance liquid
chromatography (dHPLC) was performed using the WAVE system
(Transgenomic). Samples showing unique profiles were sequenced in
both directions on ABI Prism 310 Genetic Analyzer (Applied Biosystems).
Altogether 10 previously reported changes and 8 novel genetic alterations
in MYH gene, mostly in intronic sequences were identified.
Supported by the VZ MSM0021620808 of the Czech Republic.
P0550. Florescent in situ hybridization (FISH) for the detection
of Ph- positive clone in CML: Comparison with metaphases
banding analysis
A. Movafagh, I. F. Isfahani;
Shahid Beheshti Medical University, Tehran, Islamic Republic of Iran.
Introduction: Chronic Meyloid Leukemia(CML) is characterized by
the formation of BCR/ABL fusion gene, usually as a result of the
Philadelphia(Ph) translocation between chromosomes 9 and 22.CML
is characterized by the Philadelphia in more than 90% of cases. Material
and method : In this study, we present our results of cytogenetic
analysis with GTG banding and Fluorescent in situ hybridization(FISH)
using dual color dual fusion probe CML patients registered at Taleghani
hospital from March 2004 to March 2006 ,IRAN.
Results: GTG banding metaphases was Carried out in 30 Patients
Blood /Bone marrow. Ph translocation showed in 26(87%). About
23(76.6%) of Ph- positive patients displayed the typical D-FISH signal
pattern, 17 included metaphase FISH and the rest has only interphase
FISH results.
Conclusion: Fluorescence in situ hybridization has become a widely
used method for studying Ph translocation .
P0551. The role of CDH1 gene variants in inherited
predisposition to gastric cancer
A. S. Tsukanov1 , N. I. Pospekhova1 , L. N. Lubchenko2 , M. P. Nikulin2 , R. F.
Garkavtseva2 , E. K. Ginter1 , A. V. Karpukhin1 ;
1 2 Research Centre For Medical Genetics, Moscow, Russian Federation, Cancer
Research Centre, Moscow, Russian Federation.
The CDH1 gene is a main suppressor of inherited gastric cancer. Nevertheless
only a small faction of familial gastric cancer cases is due
to CDH1 mutations. The genetic reason for the other inherited gastric
cancer cases is unknown at present time. One possibility is that CDH1
variants confer gastric cancer risk. In particulary it is known that CDH1
-160C/A promoter polymorphism is connected with functional activity
of CDH1.
We investigated significance of CDH1 -160C/A and 2076C/T SNPs for
1