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      Mutational landscape and significance across 12 major cancer types

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          Abstract

          The Cancer Genome Atlas (TCGA) has used the latest sequencing and analysis methods to identify somatic variants across thousands of tumours. Here we present data and analytical results for point mutations and small insertions/deletions from 3,281 tumours across 12 tumour types as part of the TCGA Pan-Cancer effort. We illustrate the distributions of mutation frequencies, types and contexts across tumour types, and establish their links to tissues of origin, environmental/carcinogen influences, and DNA repair defects. Using the integrated data sets, we identified 127 significantly mutated genes from well-known(forexample, mitogen-activatedprotein kinase, phosphatidylinositol-3-OH kinase,Wnt/β-catenin and receptor tyrosine kinase signalling pathways, and cell cycle control) and emerging (for example, histone, histone modification, splicing, metabolism and proteolysis) cellular processes in cancer. The average number of mutations in these significantly mutated genes varies across tumour types; most tumours have two to six, indicating that the numberof driver mutations required during oncogenesis is relatively small. Mutations in transcriptional factors/regulators show tissue specificity, whereas histone modifiers are often mutated across several cancer types. Clinical association analysis identifies genes having a significant effect on survival, and investigations of mutations with respect to clonal/subclonal architecture delineate their temporal orders during tumorigenesis. Taken together, these results lay the groundwork for developing new diagnostics and individualizing cancer treatment.

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          Most cited references 12

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          The Hallmarks of Cancer

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            The genomic landscapes of human breast and colorectal cancers.

            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.
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              The biology of chromatin remodeling complexes.

              The packaging of chromosomal DNA by nucleosomes condenses and organizes the genome, but occludes many regulatory DNA elements. However, this constraint also allows nucleosomes and other chromatin components to actively participate in the regulation of transcription, chromosome segregation, DNA replication, and DNA repair. To enable dynamic access to packaged DNA and to tailor nucleosome composition in chromosomal regions, cells have evolved a set of specialized chromatin remodeling complexes (remodelers). Remodelers use the energy of ATP hydrolysis to move, destabilize, eject, or restructure nucleosomes. Here, we address many aspects of remodeler biology: their targeting, mechanism, regulation, shared and unique properties, and specialization for particular biological processes. We also address roles for remodelers in development, cancer, and human syndromes.
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                Author and article information

                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                12 February 2014
                17 October 2013
                18 February 2014
                : 502
                : 7471
                : 333-339
                Affiliations
                [1 ]The Genome Institute, Washington University in St Louis, Missouri 63108, USA.
                [2 ]Department of Computer Science, Brown University, Providence, Rhode Island 02912, USA.
                [3 ]Department of Genetics, Washington University in St Louis, Missouri 63108, USA.
                [4 ]Department of Medicine, Washington University in St Louis, Missouri 63108, USA.
                [5 ]Siteman Cancer Center, Washington University in St Louis, Missouri 63108, USA.
                [6 ]Department of Mathematics, Washington University in St Louis, Missouri 63108, USA.
                Author notes
                Correspondence and requests for materials should be addressed to L.D. ( lding@ 123456genome.wustl.edu ).
                Article
                NIHMS550175
                10.1038/nature12634
                3927368
                24132290
                ©2013 Macmillan Publishers Limited. All rights reserved

                This work is licensed under a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported licence. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-sa/3.0

                Funding
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: U54 HG003079 || HG
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: U01 HG006517 || HG
                Funded by: National Human Genome Research Institute : NHGRI
                Award ID: R01 HG005690 || HG
                Funded by: National Cancer Institute : NCI
                Award ID: R01 CA180006 || CA
                Funded by: National Cancer Institute : NCI
                Award ID: P01 CA101937 || CA
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