Genomic instability is a characteristic of practically all human cancers. Recent results generated by members of this Consortium suggest that signs of genomic instability are evident from the very beginning of human cancer development, even in precancerous lesions. In these early lesions, the genomic instability affects primarily specific genomic loci, called common fragile sites. Because common fragile sites are very sensitive to perturbations in DNA replication, we proposed that cancer development from its very beginning is associated with DNA replication stress. A separate set of observations focused on telomeres and showed that short telomeres mimick DNA ends, activate the DNA damage checkpoint and promote genomic instability and cancer development. We propose here to study the role of DNA replication stress and short telomeres on driving genomic instability particularly in human precancerous lesions. Our studies will investigate the most common forms of cancer in the EU and will benefit from access to some of the largest databases of cancerous and precancerous lesions in Europe. Genomic instability will be explored using high resolution genomic arrays and the data will be correlated to clinical information on tumor progression. Further, analysis of proteins and genes involved in the cellular response to DNA replication stress and short telomeres will be explored using high throughput and targeted approaches and will be used to identify novel targets for cancer therapy.
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