Fragile sites in cancer: more than meets the eye

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

Vassilis G. Gorgoulis, Leandros-Vassilios Vassiliou, Panagiotis Karakaidos … (2005)

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.

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Signatures of mutation and selection in the cancer genome.

Graham Bignell, Chris Greenman, Helen Davies … (2010)

The cancer genome is moulded by the dual processes of somatic mutation and selection. Homozygous deletions in cancer genomes occur over recessive cancer genes, where they can confer selective growth advantage, and over fragile sites, where they are thought to reflect an increased local rate of DNA breakage. However, most homozygous deletions in cancer genomes are unexplained. Here we identified 2,428 somatic homozygous deletions in 746 cancer cell lines. These overlie 11% of protein-coding genes that, therefore, are not mandatory for survival of human cells. We derived structural signatures that distinguish between homozygous deletions over recessive cancer genes and fragile sites. Application to clusters of unexplained homozygous deletions suggests that many are in regions of inherent fragility, whereas a small subset overlies recessive cancer genes. The results illustrate how structural signatures can be used to distinguish between the influences of mutation and selection in cancer genomes. The extensive copy number, genotyping, sequence and expression data available for this large series of publicly available cancer cell lines renders them informative reagents for future studies of cancer biology and drug discovery.

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Chromosome fragile sites.

Sandra Durkin, Thomas Glover (2007)

Chromosomal fragile sites are specific loci that preferentially exhibit gaps and breaks on metaphase chromosomes following partial inhibition of DNA synthesis. Their discovery has led to novel findings spanning a number of areas of genetics. Rare fragile sites are seen in a small proportion of individuals and are inherited in a Mendelian manner. Some, such as FRAXA in the FMR1 gene, are associated with human genetic disorders, and their study led to the identification of nucleotide-repeat expansion as a frequent mutational mechanism in humans. In contrast, common fragile sites are present in all individuals and represent the largest class of fragile sites. Long considered an intriguing component of chromosome structure, common fragile sites have taken on novel significance as regions of the genome that are particularly sensitive to replication stress and that are frequently rearranged in tumor cells. In recent years, much progress has been made toward understanding the genomic features of common fragile sites and the cellular processes that monitor and influence their stability. Their study has merged with that of cell cycle checkpoints and DNA repair, and common fragile sites have provided insight into understanding the consequences of replication stress on DNA damage and genome instability in cancer cells.