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【medical-news】science:癌基因和抑癌基因变异的基因
Ludwig Center for Cancer Genetics and Therapeutics and Howard Hughes Medical Institute at Johns Hopkins Kimmel Cancer Center, Baltimore, MD 21231, USA.
Human cancer is caused by the accumulation of mutations in oncogenes and tumor suppressor genes. To catalog the genetic changes that occur during tumorigenesis, we isolated DNA from 11 breast and 11 colorectal tumors and determined the sequences of the genes in the Reference Sequence database in these samples. Based on analysis of exons representing 20,857 transcripts from 18,191 genes, we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. We describe statistical and bioinformatic tools that may help identify mutations with a role in tumorigenesis. These results have implications for understanding the nature and heterogeneity of human cancers and for using personal genomics for tumor diagnosis and therapy.
we conclude that the genomic landscapes of breast and colorectal cancers are composed of a handful of commonly mutated gene "mountains" and a much larger number of gene "hills" that are mutated at low frequency. nature上相似的报道
Patterns of somatic mutation in human cancer genomes.
Cancer Genome Project, Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SA, UK.
Cancers arise owing to mutations in a subset of genes that confer growth advantage. The availability of the human genome sequence led us to propose that systematic resequencing of cancer genomes for mutations would lead to the discovery of many additional cancer genes. Here we report more than 1,000 somatic mutations found in 274 megabases (Mb) of DNA corresponding to the coding exons of 518 protein kinase genes in 210 diverse human cancers. There was substantial variation in the number and pattern of mutations in individual cancers reflecting different exposures, DNA repair defects and cellular origins. Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. Systematic sequencing of cancer genomes therefore reveals the evolutionary diversity of cancers and implicates a larger repertoire of cancer genes than previously anticipated.
Most somatic mutations are likely to be 'passengers' that do not contribute to oncogenesis. However, there was evidence for 'driver' mutations contributing to the development of the cancers studied in approximately 120 genes. NATURE中的评论
Nature 446, 145-146 (8 March 2007) | doi:10.1038/446145a; Published online 7 March 2007
Cancer: Drivers and passengers
Daniel A. Haber1 and Jeff Settleman1
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Abstract
Studies that have provided the first unbiased, large-scale analyses of DNA mutations across an array of cancers also have lessons for the proposal to annotate the entire cancer genome.
Cancer results from an accumulation of mutations and other heritable changes in susceptible cells. So far, abnormalities in about 350 genes have been implicated in human cancers, but the true number of 'cancer genes' is unknown. On page 153 of this issue, Greenman and colleagues1 build on their previous analyses of breast, lung and brain tumours2, 3, 4 by identifying mutations in the genes encoding all known protein kinases — enzymes that regulate other proteins through the addition of a phosphate residue — across various types of cancer. Together with a whole-genome resequencing analysis of a smaller number of breast and colorectal cancers published by Sjöblom et al.5 in October 2006, this study presents a largely unbiased overview of the spectrum of mutations in human cancers.
Greenman and co-workers1 undertook a comprehensive sequencing of 518 protein-kinase-encoding genes in 210 cancers. Kinases have been implicated in many aspects of tumorigenesis and several have now been validated as targets for drug therapy. The spectacular success of the drug imatinib (Gleevec) in treating chronic myeloid leukaemia stems from its suppression of a kinase known as BCR–ABL, which is the product of a gene located within a cancer-specific, translocated chromosome6. In their analysis of the collection of cellular kinases, the 'kinome', Greenman et al. identified 1,000 mutations. Mutations were relatively common in cancers of the lung, stomach, ovary, colon and kidney, and rare in cancers of the testis and breast, and in carcinoid tumours, which are usually found in the gastrointestinal tract. Tumours with defects in DNA-mismatch repair harboured large numbers of mutations, whereas other types of tumour revealed no detectable mutations. Specific patterns of nucleotide substitution differed among cancers from various tissue types, possibly reflecting the effects of external mutagens or defects in DNA repair.
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作者:admin@医学,生命科学 2010-11-13 17:11
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