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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 39

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          The hallmarks of cancer.

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            Comprehensive molecular portraits of human breast tumors

            Summary We analyzed primary breast cancers by genomic DNA copy number arrays, DNA methylation, exome sequencing, mRNA arrays, microRNA sequencing and reverse phase protein arrays. Our ability to integrate information across platforms provided key insights into previously-defined gene expression subtypes and demonstrated the existence of four main breast cancer classes when combining data from five platforms, each of which shows significant molecular heterogeneity. Somatic mutations in only three genes (TP53, PIK3CA and GATA3) occurred at > 10% incidence across all breast cancers; however, there were numerous subtype-associated and novel gene mutations including the enrichment of specific mutations in GATA3, PIK3CA and MAP3K1 with the Luminal A subtype. We identified two novel protein expression-defined subgroups, possibly contributed by stromal/microenvironmental elements, and integrated analyses identified specific signaling pathways dominant in each molecular subtype including a HER2/p-HER2/HER1/p-HER1 signature within the HER2-Enriched expression subtype. Comparison of Basal-like breast tumors with high-grade Serous Ovarian tumors showed many molecular commonalities, suggesting a related etiology and similar therapeutic opportunities. The biologic finding of the four main breast cancer subtypes caused by different subsets of genetic and epigenetic abnormalities raises the hypothesis that much of the clinically observable plasticity and heterogeneity occurs within, and not across, these major biologic subtypes of breast cancer.
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              Comprehensive Molecular Characterization of Human Colon and Rectal Cancer

              Summary To characterize somatic alterations in colorectal carcinoma (CRC), we conducted genome-scale analysis of 276 samples, analyzing exome sequence, DNA copy number, promoter methylation, mRNA and microRNA expression. A subset (97) underwent low-depth-of-coverage whole-genome sequencing. 16% of CRC have hypermutation, three quarters of which have the expected high microsatellite instability (MSI), usually with hypermethylation and MLH1 silencing, but one quarter has somatic mismatch repair gene mutations. Excluding hypermutated cancers, colon and rectum cancers have remarkably similar patterns of genomic alteration. Twenty-four genes are significantly mutated. In addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found frequent mutations in ARID1A, SOX9, and FAM123B/WTX. Recurrent copy number alterations include potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2. Recurrent chromosomal translocations include fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest new markers for aggressive CRC and important role for MYC-directed transcriptional activation and repression.
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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 ).
                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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