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Polymorphic variations in apoptotic genes and cancer predisposition

Objective

The efficiency of DNA damage response is a subject of normal populational variations. The reduced ability to combat DNA alterations is associated with cancer susceptibility and can be attributed either to deficient DNA repair or, alternatively, to suboptimal cell death capacity. While the relationships between cancer risk and polymorphism of DNA repair genes are being intensively studied, the alternative aspect of the DNA damage response, i.e. apoptosis, has been unjustly overlooked in the research of tumour-associated gene polymorphisms.

This project is aimed at testing the hypothesis whether single nucleotide polymorphisms (SNPs) associated with the reduced apoptotic capacity contribute to the increased cancer risk. The following activities will be carried out:
1) Identification and validation of functional and tagging SNPs in apoptosis genes:
a) Identification of already known SNPs in research publications and Internet databases;
b) Validation of the occurrence of 'dubious' SNP by real-time AS-PCR genotyping;
c) Search for the new SNPs in previously non-tested genes by direct DNA sequencing.
2) Study on the role of apoptosis-related SNPs in cancer predisposition:
a) Preliminary study of the involvement of SNP candidates in breast cancer (BC) and lung cancer (LC) susceptibility: 'comparison of extremes' approach;
b) Traditionally designed, large case-control study for the promising SNP candidates. 3) Study on the functional significance of SNPs in apoptotic genes: analysis of correlation between individual genotype and the extent of apoptosis in lymphocytes exposed to DNA damaging dose of ionizing radiation.
4) Comparison of the rate of DNA damage induced apoptosis in lymphocytes isolated from cancer patients vs. healthy controls.
5) Comparison of radiation-induced transcriptional activation of apoptotic genes in 'high' vs. 'poor' apoptotic responders using cDNA array profiling and RT-PCR analysis.

If successful, the project will significantly improve the fundamental understanding of mechanisms of cancer susceptibility as well as facilitate the development of practical approaches for the detection of at-risk individuals.

Coordinator

LEIDEN UNIVERSITY MEDICAL CENTER

Address

Albinusdreef, 2
Leiden

Netherlands

Administrative Contact

Peter DEVILEE

Participants (4)

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FINNISH INSTITUTE OF OCCUPATIONAL HEALTH (FIOH)

Finland

KAROLINSKA INSTITUTE

Sweden

PETROV INSTITUTE OF ONCOLOGY

Russia

THE NORWEGIAN RADIUM HOSPITAL, INSTITUTE FOR CANCER RESEARCH

Norway

Project information

Grant agreement ID: INTAS 2005-1000008-7870

  • Start date

    1 October 2006

  • End date

    31 March 2009

Funded under:

IC-INTAS

  • Overall budget:

    € 106 000

  • EU contribution

    € 150 000

Coordinated by:

LEIDEN UNIVERSITY MEDICAL CENTER

Netherlands