FP6 priority

1.1.1   Genomics and Biotechnology for Health

1.1.2.2

Title of the proposal

Hereditary cancer forms: biology and detection

Institute

Slovak Academy of Sciences, Cancer Research Institute
Vlarska 7, 83391 Bratislava, Slovak Republic

Contact

Research subject for a potential FP6 project

The research interest of the department is focused on three hereditary forms of cancer: familiar adenomatous polyposis (FAP), hereditary nonpolyposis colorectal cancer (HNPCC), and hereditary breast and ovarian cancer. The main aim of previous years was to establish methods for molecular genetic diagnosis of these cancers to enable identification of Slovak families at risk. We use PTT test, SSCP, and/or fluorescence DNA sequencing analysis for mutation screening. Untill now, 85 FAP suscepted families had been screened for mutations in the largest exon 15 of APC gene, where 27 mutations were detected. The FAP patients with atypical progress of disease are studied in details. We also proceed to mutation analysis of exons 1-14 of APC gene in order to complete FAP diagnostics. HNPCC diagnosis is performed in two steps: screening of micro-satellite instability and mutation mapping by direct genomic sequencing of hMLH1 and hMSH2 genes, respectively. Recently, our department is involved in the 5^th Framework program of European Union. The project is focused on the “Novel approaches towards the diagnosis and therapy of tumours with microsatellite instability” and involves seven different european laboratories. It is aimed to develop a novel phenotype-based screening method for pre-sympto-matic identification of HNPCC patients, which would avoid flaws that are associated with the curent genotype-based screening methods. The molecular-genetic diagnostics of hereditary breast and ovarian cancers is also in progress. Up to 10% of breast and ovarian cancers are thought to be associated with hereditary lineage and most of these (~75%) are related to mutations in the BRCA1and BRCA2 genes. Thus it is of our particular interest to identify patho-genic mutations in these genes and facilitate early diagnosis of the breast and ovarian cancer in slovak families at risk. We also plan to search for and study the role as well as interplay of polymorfisms of APC and HNPCC genes, mechanisms of wild type allele inactivation during HNPCC development and promoter methylation profiles in several presented genes. It is of our eminent interest to participate on the projects aiming to improve molecular-genetic diagnostics assays for FAP, HNPCC and hereditary breast and ovarian cancers as well as the projects on the gene alterations studies helping to understand hereditary cancer biology.

Recent international cooperation of the research team

Carl`s University, Institute of Medical Biology and Genetics, Hradec Kralove, Czech Republic; AKH Vienna, Austria; Institute of Medical Radiobiology, University of Zurich, Switzerland; University of Leiden, The Netherlands; University of Helsinki, Finland

Proposer´s relevant publications related to the research subject

Zajac, V., Tomka, M., Ilencikova, D., Majek, J., Stevurkova, V., Kirchhoff, T.: A double germline mutations in the APC and p53 genes. Neoplasma, 47, 335-341, 2000.
Marra, G., D`Atri, S., Corti, Ch., Bonmassar, L., Cattaruzza, M.S., Schweizer, P., Heinimann, K., Bartosova, Z., Nystrom-Lahti, M., Jiricny, J.: Tolerance of human hMSH2^+/- lymphoblastoid cells to the methylating agent temozolomide. PNAS, 98, 7164-7169, 2001.
Tomka, M., Sedlakova, O., Reinerova, M., Veselovska, Z., Stevurkova, V., Bartosova, Z., Zajac, V.: Mutation screening of the BRCA1 gene in Slovak patients. Neoplasma, 48, 451-455, 2001