Next Generation Sequencing: Current realities in cancer biology

16 February 2011  •  Author(s): Ross Sibson, Director of Research, Applied Cancer Biology Group, University of Liverpool

The rate of progress in molecular cell biological sciences has become dramatic. This is fuelled in part by developments in technology, none more so than in the field of nucleic acid sequencing. So-called Next Generation Sequencing Platforms promise to revolutionise our understanding of the importance of genetic differences on an individual basis. According to the modern personalised or stratified medicine paradigms, this will revolutionise current practices in terms of early detection, treatment, diagnosis, prognosis and even prevention. Revolutions are apt to disappoint and drug pipelines have yet to justify such optimism yet molecular geneticists can point already to notable successes like the completion of their flagship project, the human genome in 2001, within time and within budget. What are the current realities? The field of cancer serves as an excellent test and would suggest that advances are being made incrementally but rapidly.

Cancer is a genetic disease in which inheritance can play a part. The huge complexity of acquired genetic changes is however of major importance. Functional consequences for a subset of these changes have already been determined and efficacious new molecular therapies brought to patients as a consequence. Herceptin targeting of the HER2 receptor in breast, Erbitux targeting of the EGFR receptor in colorectal and Gleevec targeting of the BCR-ABL gene fusion products in chronic myelogenous leukemia all serve as paradigms of how knowledge about underlying oncogenic changes at the genetic level can be exploited to develop targeted therapies for use on a personalised basis, dependent on the presence of the alteration within individual patients. A major remaining challenge is to understand and act on the overwhelming remainder of the complexity which varies markedly on an individual basis and contributes to the development of resistance mechanisms.

First, it is useful to consider the progress already made using previous technologies including Sanger dideoxy sequencing, the almost exclusive method for over 30 years. Despite the limitation of older technologies, they have still been able to yield important insights into the significance of genetic changes in cancer and provide a platform on which the newer technologies can build. Sequencing studies have largely screened for mutations in exonic regions because of their presumed functional importance. Long, accurate read lengths allowed large PCR amplified regions from genes of interest to be read in a high throughput manner achieved by batch processes borrowed from the human genome sequencing project. Early comprehensive studies examined gene families, in particular the protein kinase superfamily because it contains many important effecter molecules implicated in cancer. The ‘kinome’ of 25 primary breast cancers yielded 92 somatic mutations1. These were distributed unevenly between patients with almost half not yielding a mutation and over half of the mutations occurring in one individual, suggestive of a novel mutator phenotype in the latter. There was a significant excess of non synonymous mutations, suggesting that a subset contribute to cancer development, so called ‘drivers’ and the converse that not all changes are relevant, so-called ‘passengers’ that owe their existence to co-occurrence with positively selected changes.

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