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

Abstract

Two groups this week report findings that could have a big impact on our view of cancer development. Both looked at tumours (bladder, breast and colorectal, and in lung and skin) in various stages of progression for signs of a DNA damage response. And both find that early stages of cancer development are associated with an active DNA damage response and p53-dependent cell death. This suggests that the induction of a DNA damage response by oncogenic events is a potent tumour suppression mechanism, and explains the selective pressure for p53 mutations in precancerous lesions. Importantly, activation of the DNA damage checkpoint occurs before chromosome instability and malignancy. On the cover, 53BP1 foci in lung hyperplasia (green indicates DNA damage checkpoint activation). 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.