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Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

Abstract

DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive1,2,3. 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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Figure 1: Activation of the DNA double-strand break (DSB) checkpoint pathway in human preneoplastic and neoplastic lesions.
Figure 2: Summary of DNA double-strand break responses in human normal tissues, preneoplastic lesions and neoplastic lesions.
Figure 3: Activation of the DNA DSB checkpoint pathway in experimentally induced hyperplasias.
Figure 4: Allelic imbalance at common fragile sites in early human cancer lesions and model for activation of the DNA DSB checkpoint in cancer.

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Acknowledgements

The authors thank R. Kaufman, L. Kaklamanis, M. Arnaouti, P. Foukas, K. Ryan and V. Kostaki for support, reagents and tissue samples. This work was supported by grants to T.D.H. from the National Cancer Institute and to T.L. from the Roy Castle Lung Foundation, UK. M.V. was supported by a Radiation training grant from the NIH.

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Correspondence to Thanos D. Halazonetis.

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Gorgoulis, V., Vassiliou, LV., Karakaidos, P. et al. Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions. Nature 434, 907–913 (2005). https://doi.org/10.1038/nature03485

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