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Journeys into the genome of cancer cells.

Stratton MR - EMBO Mol Med (2013)

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. mrs@sanger.ac.uk

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Instead, I decided to explore the possibility that a further high-risk breast cancer susceptibility gene existed, although the evidence for this was by no means definitive... Nevertheless, after a couple of years acquiring breast cancer families that did not seem to be due to BRCA1, Richard Wooster (then a post doc with me) and the group embarked on another genome-wide search by genetic linkage analysis (in collaboration with David Goldgar and others) and ultimately located BRCA2 in 1994 to chromosome 13q, in the process of course, also proving that the second gene existed (Wooster et al, )... In this undertaking, we ourselves were now ensnared in a cloning race because we disagreed with the gene patenting and monopolization policies of Myriad Genetics, a biotechnology company from Utah, who became our competitors... Although the outlook initially did not look optimistic, we forged a collaboration with many participants, notably including Alan Ashworth, Andy Futreal and David Bentley (at the then Sanger Centre) and won the race at the end of 1995 (Wooster et al, )... Following the identification of BRCA2, we set off on a search for yet another high risk breast cancer gene, ‘BRCA3’... Unfortunately, this transpired to be a fruitless endeavour and the general conclusion now is that only two such genes exist... Nevertheless, a few years later with Nazneen Rahman, my erstwhile PhD student who was now leading the breast cancer genetics group at the Institute of Cancer Research, we started systematically sequencing candidate genes that were part of the DNA damage and repair pathways that include BRCA1/2 and identified a number of intermediate risk (two- to fourfold) breast cancer susceptibility genes including CHEK2, ATM, BRIP1 and PALB2... Towards the end of the last millennium, it was becoming apparent that most high-risk cancer susceptibility genes had been found... However, the nature of BRAF and its mutations recommended it as a drug target... In work conducted by others over the subsequent decade, small molecule inhibitors of mutated BRAF have been derived and shown to be effective in patients with metastatic malignant melanoma... A small number of cancer genes are mutated frequently, but many appear to contribute infrequently to cancer development (Greenman et al, )... Using these approaches, with Peter Campbell joining us at Sanger, we have been able to explore cancer genomes at sequence-level resolution revealing their extraordinarily contorted architecture (Fig 2; Stephens et al, ), producing essentially complete catalogues of somatic mutations from individual human cancers (Pleasance et al, ) and yielding many new mutated cancer genes (Stephens et al, )... Cancer genomics is already established in the clinical management of patients, as tests for mutations in certain genes, for example EGFR, BRAF and HER2, are required before drugs targeting the encoded protein can be prescribed... Over the next few years, the complete repertoire of mutated cancer genes across the spectrum of cancer types will be identified... At the same time, deeper understanding of the mechanisms underlying the processes generating somatic mutations will lead to new insights into cancer causation and, potentially, new preventive strategies.

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The genome-wide rearrangements in six breast cancer genomes (three cell lines, top and three primary tumours, below)In each case, the genome is represented as a circle and the lines represent somatic rearrangements, green are intrachromosomal and purple interchromosomal. First published in Stephens et al (2009).
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fig02: The genome-wide rearrangements in six breast cancer genomes (three cell lines, top and three primary tumours, below)In each case, the genome is represented as a circle and the lines represent somatic rearrangements, green are intrachromosomal and purple interchromosomal. First published in Stephens et al (2009).

Mentions: The advent of next generation sequencing technologies around 2007 transformed our studies, and the field in general. Using these approaches, with Peter Campbell joining us at Sanger, we have been able to explore cancer genomes at sequence-level resolution revealing their extraordinarily contorted architecture (Fig 2; Stephens et al, 2009), producing essentially complete catalogues of somatic mutations from individual human cancers (Pleasance et al, 2010) and yielding many new mutated cancer genes (Stephens et al, 2012).


Journeys into the genome of cancer cells.

Stratton MR - EMBO Mol Med (2013)

The genome-wide rearrangements in six breast cancer genomes (three cell lines, top and three primary tumours, below)In each case, the genome is represented as a circle and the lines represent somatic rearrangements, green are intrachromosomal and purple interchromosomal. First published in Stephens et al (2009).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3569633&req=5

fig02: The genome-wide rearrangements in six breast cancer genomes (three cell lines, top and three primary tumours, below)In each case, the genome is represented as a circle and the lines represent somatic rearrangements, green are intrachromosomal and purple interchromosomal. First published in Stephens et al (2009).
Mentions: The advent of next generation sequencing technologies around 2007 transformed our studies, and the field in general. Using these approaches, with Peter Campbell joining us at Sanger, we have been able to explore cancer genomes at sequence-level resolution revealing their extraordinarily contorted architecture (Fig 2; Stephens et al, 2009), producing essentially complete catalogues of somatic mutations from individual human cancers (Pleasance et al, 2010) and yielding many new mutated cancer genes (Stephens et al, 2012).

View Article: PubMed Central - PubMed

Affiliation: Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, UK. mrs@sanger.ac.uk

AUTOMATICALLY GENERATED EXCERPT
Please rate it.

Instead, I decided to explore the possibility that a further high-risk breast cancer susceptibility gene existed, although the evidence for this was by no means definitive... Nevertheless, after a couple of years acquiring breast cancer families that did not seem to be due to BRCA1, Richard Wooster (then a post doc with me) and the group embarked on another genome-wide search by genetic linkage analysis (in collaboration with David Goldgar and others) and ultimately located BRCA2 in 1994 to chromosome 13q, in the process of course, also proving that the second gene existed (Wooster et al, )... In this undertaking, we ourselves were now ensnared in a cloning race because we disagreed with the gene patenting and monopolization policies of Myriad Genetics, a biotechnology company from Utah, who became our competitors... Although the outlook initially did not look optimistic, we forged a collaboration with many participants, notably including Alan Ashworth, Andy Futreal and David Bentley (at the then Sanger Centre) and won the race at the end of 1995 (Wooster et al, )... Following the identification of BRCA2, we set off on a search for yet another high risk breast cancer gene, ‘BRCA3’... Unfortunately, this transpired to be a fruitless endeavour and the general conclusion now is that only two such genes exist... Nevertheless, a few years later with Nazneen Rahman, my erstwhile PhD student who was now leading the breast cancer genetics group at the Institute of Cancer Research, we started systematically sequencing candidate genes that were part of the DNA damage and repair pathways that include BRCA1/2 and identified a number of intermediate risk (two- to fourfold) breast cancer susceptibility genes including CHEK2, ATM, BRIP1 and PALB2... Towards the end of the last millennium, it was becoming apparent that most high-risk cancer susceptibility genes had been found... However, the nature of BRAF and its mutations recommended it as a drug target... In work conducted by others over the subsequent decade, small molecule inhibitors of mutated BRAF have been derived and shown to be effective in patients with metastatic malignant melanoma... A small number of cancer genes are mutated frequently, but many appear to contribute infrequently to cancer development (Greenman et al, )... Using these approaches, with Peter Campbell joining us at Sanger, we have been able to explore cancer genomes at sequence-level resolution revealing their extraordinarily contorted architecture (Fig 2; Stephens et al, ), producing essentially complete catalogues of somatic mutations from individual human cancers (Pleasance et al, ) and yielding many new mutated cancer genes (Stephens et al, )... Cancer genomics is already established in the clinical management of patients, as tests for mutations in certain genes, for example EGFR, BRAF and HER2, are required before drugs targeting the encoded protein can be prescribed... Over the next few years, the complete repertoire of mutated cancer genes across the spectrum of cancer types will be identified... At the same time, deeper understanding of the mechanisms underlying the processes generating somatic mutations will lead to new insights into cancer causation and, potentially, new preventive strategies.

Show MeSH
Related in: MedlinePlus