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Genomic instability — an evolving hallmark of cancer

Nature Reviews Molecular Cell Biology volume 11, pages 220–228 (2010)Cite this article

Subjects

Key Points

  • Genomic instability is a characteristic of most cancers. Insight into the possible mechanisms leading to genomic instability can be gained by reviewing the recent high-throughput sequencing studies of human cancers.

  • In hereditary cancers, characterized either by microsatellite instability or chromosomal instability, the underlying basis for the genomic instability is mutations in DNA repair genes.

  • In sporadic (non-hereditary) cancers, genomic instability, at least at the early stages of cancer development, is not due to mutations in DNA repair genes or mitotic checkpoint genes.

  • The pattern of mutations in sporadic human cancers suggests that the selective pressure for tumour suppressor p53 (TP53) mutations is linked to DNA damage, rather than p14ARF activation.

  • Genomic instability in sporadic human cancers may be linked to oncogene-induced DNA damage.

  • Analysis of the recent high-throughput sequencing studies of human cancers suggests that genomic instability can be added to the original hallmarks of cancer, and that two previously distinct hallmarks, self-sufficiency in growth signals and insensitivity to anti-growth signals, can be consolidated into one.

Abstract

Genomic instability is a characteristic of most cancers. In hereditary cancers, genomic instability results from mutations in DNA repair genes and drives cancer development, as predicted by the mutator hypothesis. In sporadic (non-hereditary) cancers the molecular basis of genomic instability remains unclear, but recent high-throughput sequencing studies suggest that mutations in DNA repair genes are infrequent before therapy, arguing against the mutator hypothesis for these cancers. Instead, the mutation patterns of the tumour suppressor TP53 (which encodes p53), ataxia telangiectasia mutated (ATM) and cyclin-dependent kinase inhibitor 2A (CDKN2A; which encodes p16INK4A and p14ARF) support the oncogene-induced DNA replication stress model, which attributes genomic instability and TP53 and ATM mutations to oncogene-induced DNA damage.

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Figure 1: Mutations in p53 pathway genes are mutually exclusive with ATM, but not CDKN2A, mutations.
Figure 2: Genomic instability as a hallmark of cancer.

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Acknowledgements

The authors thank B. Zhivotovsky for comments on the manuscript. Research in the laboratories of the authors is supported by the EC project GENICA, the Swiss National Science Foundation and the National Institutes of Health, USA.

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Authors and Affiliations

  1. Department of Molecular Biology, CH-1205, Geneva, Switzerland

    Simona Negrini & Thanos D. Halazonetis

  2. Department of Biochemistry, University of Geneva, CH1205, Geneva, Switzerland

    Vassilis G. Gorgoulis

  3. Department of Histology and Embryology, School of Medicine, University of Athens, GR-11527, Athens, Greece

    Thanos D. Halazonetis

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  1. Simona Negrini
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Correspondence to Thanos D. Halazonetis.

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The Cancer Genome Atlas

Glossary

Hereditary non-polyposis colon cancer

An autosomal dominant disease that is characterized by increased susceptibility to colon carcinoma and other forms of cancer owing to an inherited defect in DNA mismatch repair genes.

DNA mismatch repair

The repair of DNA base-pair mismatches that arise as a result of replication errors or after exposure to several DNA damaging agents.

MYH-associated polyposis

An autosomal recessive disease that predisposes to colorectal cancer and is caused by germline mutations in the DNA repair gene MYH.

Base excision repair

A pathway of DNA repair in which a single damaged base is excised by a DNA glycosylase.

Fanconi anaemia

A rare autosomal recessive disease that is characterized by developmental abnormalities, aplastic anaemia and increased susceptibility to solid and haematopoietic cancers.

Xenograft

A tissue or organ from one species transplanted into another species. The term is derived from the Greek 'Xeno', meaning foreign, and graft.

Glioblastoma

The most frequent and most malignant type of primary brain cancer. It is composed of poorly differentiated neoplastic astrocytes.

Transcription coupled-nucleotide excision repair

The branch of nucleotide excision repair — a pathway that repairs damaged bases by excision of a 25–30-nucleotide stretch of the DNA strand that contains the damaged base or bases — that repairs DNA lesions in the transcribed strands of active genes.

Spindle assembly checkpoint

The checkpoint that monitors the proper attachment of chromosomes to spindle microtubules.

Non-synonymous mutation

A mutation that results in an alteration of the amino acid sequence of a protein.

Fanconi anaemia DNA repair pathway

A pathway that primarily repairs DNA interstrand cross links.

Homologous recombination (HR) repair

The error-free repair of DNA DSBs, in which the broken DNA molecule is repaired using homologous sequences.

Non-homologous end joining

A pathway that repairs DNA DSBs by directly ligating the broken ends, without the need for a homologous template.

Common fragile site

A chromosomal region that is prone to breakage after inhibition of DNA replication.

Proteotoxic stress

A cellular stress that is due to the accumulation of misfolded proteins arising from disequilibrium in the protein homeostatic machinery.

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Negrini, S., Gorgoulis, V. & Halazonetis, T. Genomic instability — an evolving hallmark of cancer. Nat Rev Mol Cell Biol 11, 220–228 (2010). https://doi.org/10.1038/nrm2858

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