2009 Vienna - European Society of Human Genetics

Cancer genetics
tile polyposis. We believe that ovarian cystadenomas is another neoplastic
complication of infantile polyposis, and that our report widens a
spectrum of 10q23 microdeletion phenotype.
P06.049
international consensus for neuroblastoma molecular
diagnostics: Report from the international neuroblastoma risk
grouping (iNRG) Biology committee
P. F. Ambros 1 , I. M. Ambros 1 , G. M. Brodeur 2 , M. Haber 3 , J. Khan 4 , A. Nakagawara
5 , G. Schleiermacher 6 , F. Speleman 7 , R. Spitz 8 , W. B. London 9 , S. L.
Cohn 10 , A. D. J. Pearson 11 ;
1 CCRI, Children’s Cancer Research Institute, Vienna, Austria, 2 Center for Childhood
Cancer Research, Children’s Hospital of Philadelphia and the University
of Pennsylvania School of Medicine, PA, USA, Philadelphia, PA, United States,
3 Children´s Cancer Institute Australia, Sydney, Australia, 4 National Cancer Institute,
Bethesda, WA, United States, 5 Chiba Cancer Center Research Institute,
Chiba, Japan, 6 Institut Curie, Paris, France, 7 Centre for Medical Genetics, Ghent,
Belgium, 8 University of Cologne, Cologne, Germany, 9 Children’s Oncology
Group Statistics and Data Center, University of Florida, Gainesville, FL, United
States, 10 The University of Chicago, Chicago, IL, United States, 11 Section of
Paediatrics, Institute of Cancer Research and Royal Marsden Hospital, Surrey,
United Kingdom.
Background: Neuroblastoma serves as a paradigm for utilizing tumour
genomic data for determining patient prognosis and treatment allocation.
However, prior to the establishment of the International Neuroblastoma
Risk Group (INRG) Task Force in 2004, international consensus
on markers, methodology, and data interpretation did not exist,
compromising the reliability of decisive genetic markers and inhibiting
translational research efforts. The objectives of the INRG Biology
Committee were to identify highly prognostic genetic aberrations to be
included in the new INRG risk classification schema and to develop
precise definitions, decisive biomarkers, and technique standardization.
Methods: The review of the INRG database by the INRG Task Force
finally enabled the identification of the most significant neuroblastoma
biomarkers. In addition, the Biology Committee compared different cooperative
group standard operating procedures to arrive at international
consensus for methodology, nomenclature and future directions.
Results: Consensus was reached to include MYCN status, 11q23 allelic
status, and ploidy in the INRG Classification System based on an
evidence-based review of the INRG database. Standardized operating
procedures for analyzing these genetic factors were adopted and criteria
for proper nomenclature were developed.
Conclusions: Neuroblastoma treatment planning is highly dependant
on tumour cell genomic features, and it is likely that a comprehensive
panel of DNA-based biomarkers will be used in future risk assignment
algorithms applying genome-wide techniques. Consensus on methodology
and interpretation is essential for uniform INRG classification
and will greatly facilitate international and cooperative clinical and
translational research studies.
P06.050
study of primary and secondary tumors from patients with
laryngeal and oropharyngeal cancer - a comparative approach
A. Niculescu1 , L. Ghetea1 , R. Motoc1 , D. Manu2 ;
1 2 Institute of Genetics, University of Bucharest, Bucharest, Romania, “Ilfov”
Emergency County Hospital, Bucharest, Romania.
Our study was focused on laryngeal and oropharyngeal cancers,
which have nowadays an increased incidence, due to unhealthy habits
like tobacco and alcohol consumption. We used transmission electron
microscopy (TEM) in order to highligth the ultrastructural features of
cancer cells, in primary and secondary tumors. The differences between
the inner architecture of the tumor cells where correlated with
the expression of some genes (oncogenes and tumor suppressor factors),
in order to establish the aggressiveness of the tumor, in different
disease stages.
Primary- and secondary tumor tissues, and also non-transformed tissue
(from the vicinity of the tumor) were surgically obtained from 16
patients (8 with primary tumors and 8 with secondary tumors), from the
“Ilfov” Emergency County Hospital, Bucharest.
The most important observation made from the ultrastructural data
obtained by transmission electron microscopy is the aggressiveness
and invasiveness of this type of cancer. The TEM conclusions are sus-
tained by the overexpression of the studied oncogenes, in both type of
tumors, and also the overexpression of the studied tumoral supressor
genes, especially in primary tumors. P16 gene was underexpressed in
the tumor cells, compared to normal ones, in only one case (carcinosarcoma
tumor type). P21 gene level is decreasing in the secondary
tumors, compared to primary ones.
The studied genes proved to be good candidates as tumoral markers
in laryngeal and oropharyngeal cancer. The analysis of the combinations
between the expression level of these genes is of real relevance
for the prognosis of patient evolution and improvment of the treatment
strategies.
P06.051
LATS2 tumour specific mutations and methylation of promoter
in non-small cell carcinoma
M. Stražišar, V. Mlakar, D. Glavač;
Institute of Pathology, Faculty of Medicine, Ljubljana, Slovenia.
LATS2 is putative tumour supressor gene, involved in maintenance
of cell stability. It is situated on a chromosome location, which is in
tumours often affected by LOH. Diminished expression is detected in
different types of cancer and often related to methylation.
Fifty-one adenocarcinomas (ADC) and sixty-seven squamous cell carcinomas
(SCC) in different tumour stages and adjacent healthy lung
tissue were included in our study. LATS2 alterations were discovered
with denaturising high-pressure liquid chromatography (DHPLC). Gene
expression levels were established with real-time PCR and methylation
with restriction analysis of bisulphite treated DNA. Results from
DHPC and methylation analysis were confirmed by sequencing.
LATS2 was down regulated in ADC and SCC (Student’s t test, pC by direct sequencing of
the entire coding sequence of p53. This constitutional mutation leads
to an amino acid substitution in the protein changing arginine for proline
(p.R342P) and occurs in a region that is responsible for oligomerization.
A review of mutational p53 database UMD-p53 (Beroud and
Soussi, 2007) revealed only 4 cases of sporadic malignancies, namely
an advanced breast carcinoma, one ewing´s sarcoma and two ovarian
cancers that harbored this genetic alteration demonstrating this variant
to be pathogenic and extremely rare even in somatic malignancies. Affected
members of the here reported LFS family (LF-342-1) developed
the classical spectrum of malignancies and carried all the identical
gene alteration, indicating its transmission by inheritance and suggesting
this mutation to severely impair the physiologic function of p53.