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The Cancer Genome Project: Key achievements

The Cancer Genome Project achieved its first success in 2002 with the discovery of mutations in the BRAF gene that lead to malignant melanoma, a form of skin cancer which can be lethal. From the discoveries made with this one gene, the Project is now investigating the complete genomes of cancers.

Although malignant melanoma accounts for only 3 per cent of skin cancer cases, it is the cause of three out of four skin cancer deaths. The melanoma genome contained more than 30 000 mutations that carried a record of how and when they occurred during the patient's life. Subsequently it has been shown that the BRAF gene is mutated in 60-70 per cent of malignant melanomas and 10-15 per cent of colorectal cancers.

As part of their central aim to identify the mutated genes that are implicated in developing cancer, the Project conducted a census in 2004 of reported cancer genes in the published scientific literature. The census showed that more than 1% of all the genes in the human genome had the potential to become cancer-causing genes. The protein kinase domain - which plays a critical role in regulating the many processes of the cell - was identified as the one most commonly encoded by cancer genes. Other domains identified included several involved in the binding of DNA and the regulation of transcription - the process where a gene is converted into a message that can be translated into its protein product.

Between 2005 and 2007, the sequencing of more than 500 genes for protein kinases in 210 types of cancer, including breast, lung, colorectal and stomach cancers showed that the number of mutated genes driving the development of cancer was greater than was previously thought at the time. The Project found more than 1000 mutations in the kinase genes, which could be divided into 'drivers' and 'passengers'. Driver mutations are ones that cause cancer cells to grow, while 'passengers' - mutations that have hitchhiked along for the ride - make no contribution to cancer development. The research team identified possible driver mutations in 120 genes, most of which had not been seen before.

In 2008, a study of two individuals with lung cancer identified 103 acquired structural changes in cancer cells in a background of 306 inherited genomic rearrangments, all at base-pair resolution - demonstrating the feasibility of systematic searches for cancer-causing rearrangements. In the same year, the Project team was able to piece together the evolutionary history of the subclones - the descendants of the original cancerous cell - from 22 people with a type of leukaemia.

At the end of 2009, the Project published the first comprehensive near complete genome-wide analyses of two cancers, a small-cell lung cancer and malignant melanoma. The number of mutations found for the lung cancer suggested that a typical smoker would acquire one mutation for every 15 cigarettes smoked.

Building on the work of earlier cancer genetics research, including that of the Cancer Genome Project, the International Cancer Genome Consortium was launched in 2008 and is now working to sequence 25 000 cancer genomes, from 50 different kinds of cancer. This will identify all the driving cancer genes and provide great insight into the processes that cause cancer. The Cancer Genome Project will play its part in the sequencing of 500 breast cancers for the consortium.

See also

References

  • Davies H et al. Mutations of the BRAF gene in human cancer. Nature 2002;417(6892):949-54.
  • Futreal PA et al. A census of human cancer genes. Nat Rev Cancer. 2004 Mar;4(3):177-83.
  • Davies H et al. Somatic mutations of the protein kinase gene family in human lung cancer. Cancer Res. 2005 Sep 1;65(17):7591-5.
  • Greenman C et al. Patterns of somatic mutation in human cancer genomes. Nature 2007;446:153-8.
  • Haber DA and Settleman J. Cancer: drivers and passengers. Nature 2007;446:145-6.
  • Campbell PJ et al. Identification of somatically acquired rearrangements in cancer using genomewide massively parallel paired-end sequencing. Nat Genet 2008;40(6):722-9.
  • Campbell PJ et al. Subclonal phylogenetic structures in cancer revealed by ultra-deep sequencing. Proc Natl Acad Sci USA 2008;105(35):13081-6.
  • Pleasance ED et al. A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature 2009; 463:184-190.
  • Pleasance ED, Cheetham RK et al. A comprehensive catalogue of somatic mutations from a human cancer genome. Nature 2009; 463:191-196.
  • The International Cancer Genome Consortium. International network of cancer genome projects. Nature 2010; 464:993-998.
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