1. Department of Histology and Embryology, School of Medicine, University of Athens, Athens GR-11527, Greece
2. Roy Castle Lung Cancer Research Programme, Cancer Research Center, University of Liverpool, Liverpool L3 9TA, UK
3. The Wistar Institute, Philadelphia, Pennsylvania 19104-4268, USA
4. Graduate Group in Biomedical Sciences and
5. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
6. Department of Human Genetics, Mount Sinai School of Medicine, New York, New York 10029, USA
7. Institute of Biology, National Centre of Scientific Research 'Demokritos', Athens GR-15310, Greece
8. These authors contributed equally to this work

Correspondence to: Thanos D. Halazonetis^3,5 Correspondence and requests for materials should be addressed to T.D.H. (Email: halazonetis@wistar.upenn.edu).

DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive^{1, 2, 3}. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.

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