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Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions
Vassilis G Gorgoulis1, Leandros-Vassilios F Vassiliou, Panagiotis Karakaidos
1Department of Histology and Embryology, School of Medicine, University of Athens, Athens GR-11527, Greece.
Abstract:
DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. 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.
Insights
Cancer development begins with DNA replication stress, causing DNA damage and genomic instability. This creates pressure to inactivate key genes like p53, driving cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- DNA damage checkpoint genes, including p53, are frequently mutated in human cancers.
- The selective pressures driving the inactivation of these critical genes are not fully understood.
Purpose of the Study:
- To investigate the early events in cancer development and identify the selective pressures for p53 inactivation.
- To explore the role of DNA damage response and replication stress in pre-cancerous lesions.
Main Methods:
- Analysis of human lung hyperplasias and dysplastic nevi.
- Assessment of DNA damage response markers (histone H2AX, Chk2 phosphorylation, p53, 53BP1, apoptosis).
- Examination of allelic imbalance at common fragile sites in hyperplastic tissues.
Main Results:
- Early hyperplasias showed DNA damage response signs despite wild-type p53 and no gross chromosomal instability.
- Progression to carcinoma correlated with p53 or 53BP1 inactivation and reduced apoptosis.
- Both lung and experimentally induced skin hyperplasias exhibited allelic imbalance at common fragile sites.
Conclusions:
- Cancer development is associated with DNA replication stress from its earliest stages.
- Replication stress leads to DNA double-strand breaks and genomic instability.
- This instability creates a selective pressure for mutations in genes like p53.
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