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         description:Although a few cancer genes are mutated in a high proportion of tumours of a given type (>20%), most are mutated at intermediate frequencies (2–20%). To explore the feasibility of creating a comprehensive catalogue of cancer genes, we analysed somatic point mutations in exome sequences from 4,742 human cancers and their matched normal-tissue samples across 21 cancer types. We found that large-scale genomic analysis can identify nearly all known cancer genes in these tumour types. Our analysis also identified 33 genes that were not previously known to be significantly mutated in cancer, including genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. We estimate that near-saturation may be achieved with 600–5,000 samples per tumour type, depending on background mutation frequency. The results may help to guide the next stage of cancer genomics. Large-scale genomic analysis of somatic point mutations in exomes from tumour–normal pairs across 21 cancer types identifies most known cancer genes in these tumour types as well as 33 genes not known to be significantly mutated, and down-sampling analysis indicates that larger sample sizes will reveal many more genes mutated at clinically important frequencies. Most cancer genes are mutated at intermediate frequencies, appearing in less than one in five samples of a particular tumour type, so the accurate identification of cancer genes needs to be based on large-scale sampling in order to take account of this mutation-rate heterogeneity. This study presents a statistical analysis of 21 tumour types from more than 4,700 tumour–normal pairs. The authors identify 33 previously unknown genes related to proliferation, apoptosis, genome stability, chromatin regulation, immune evasion, RNA processing and protein homeostasis. Further analyses suggest that near-saturation may be achieved with between 600 and 5,000 samples for a given tumour type, depending on background mutation rate.
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            name:Broad Institute of MIT and Harvard, 7 Cambridge Center
            address:
               name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
               type:PostalAddress
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            name:Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA
            address:
               name:Cancer Center and Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA,
               type:PostalAddress
            type:Organization
      name:James T. Robinson
      affiliation:
            name:Broad Institute of MIT and Harvard, 7 Cambridge Center
            address:
               name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
               type:PostalAddress
            type:Organization
      name:Levi A. Garraway
      affiliation:
            name:Broad Institute of MIT and Harvard, 7 Cambridge Center
            address:
               name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
               type:PostalAddress
            type:Organization
            name:Dana-Farber Cancer Institute, 450 Brookline Avenue
            address:
               name:Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, USA
               type:PostalAddress
            type:Organization
            name:Harvard Medical School, 25 Shattuck Street
            address:
               name:Harvard Medical School, 25 Shattuck Street, Boston, USA
               type:PostalAddress
            type:Organization
      name:Todd R. Golub
      affiliation:
            name:Broad Institute of MIT and Harvard, 7 Cambridge Center
            address:
               name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
               type:PostalAddress
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            name:Dana-Farber Cancer Institute, 450 Brookline Avenue
            address:
               name:Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, USA
               type:PostalAddress
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            name:Harvard Medical School, 25 Shattuck Street
            address:
               name:Harvard Medical School, 25 Shattuck Street, Boston, USA
               type:PostalAddress
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            name:Howard Hughes Medical Institute, 4000 Jones Bridge Road
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               name:Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, USA
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            address:
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               type:PostalAddress
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            address:
               name:Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, USA
               type:PostalAddress
            type:Organization
            name:Harvard Medical School, 25 Shattuck Street
            address:
               name:Harvard Medical School, 25 Shattuck Street, Boston, USA
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      name:Stacey B. Gabriel
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            address:
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            address:
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               type:PostalAddress
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            address:
               name:Harvard Medical School, 25 Shattuck Street, Boston, USA
               type:PostalAddress
            type:Organization
            name:Massachusetts Institute of Technology, 77 Massachusetts Avenue
            address:
               name:Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, USA
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      name:Gad Getz
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            name:Broad Institute of MIT and Harvard, 7 Cambridge Center
            address:
               name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
               type:PostalAddress
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            name:Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA
            address:
               name:Cancer Center and Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA,
               type:PostalAddress
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            name:Harvard Medical School, 25 Shattuck Street
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      email:[email protected]
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      name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
      name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
      name:Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, USA
      name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
      name:Cancer Center and Department of Pathology, Massachusetts General Hospital, 55 Fruit Street, Boston, Massachusetts 02114, USA,
      name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
      name:Broad Institute of MIT and Harvard, 7 Cambridge Center, Cambridge, USA
      name:Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, USA
      name:Harvard Medical School, 25 Shattuck Street, Boston, USA
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      name:Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, USA
      name:Harvard Medical School, 25 Shattuck Street, Boston, USA
      name:Howard Hughes Medical Institute, 4000 Jones Bridge Road, Chevy Chase, USA
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