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      Comprehensive molecular characterization of gastric adenocarcinoma

      1 , 2 , 2 , 2 , 2 , 2 , 3 , 3 , 4 , 3 , 3 ,   5 , 6 , 5 , 7 , 8 , 8 , 8 , 8 , 8 , 8 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 10 , 10 , 10 , 11 , 12 , 12 , 13 , 13 , 14 , 15 , 15 , 16 , 17 , 18 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 25 , 26 , 27 , 28 , 28 , 28 , 28 , 29 , 30 , 31 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 29 , 29 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 8 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 ,   9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 9 , 32 , 13 , 13 , 33 , 32 , 32 , 32 , 13 , 32 , 33 , 33 , 32 , 13 , 33 , 32 , 13 , 13 , 32 , 33 , 13 , 10 , 10 , 10 , 10 , 10 , 11 , 11 , 11 , 11 , 3 , 3 , 3 , 3 , 3 , 3 , 3 , 3 , 34 , 34 , 9 , 32 , 9 , 9 , 9 , 5 , 5 , 5 , 5 , 5 , 5 , 5 , 5 , 5 , 5 , 5 , 5 , 5 , 5 , 5 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 2 , 21 , 21 , 21 , 10 , 10 , 10 , 10 , 10 , 32 , 11 , 25 , 25 , 25 , 35 , 28 , 28 , 28 , 28 , 28 , 28 , 28 , 28 , 28 , 28 , 28 , 28 , 36 , 36 , 36 , 36 , 36 , 36 , 36 , 36 , 36 , 36 , 36 , 37 , 38 , 39 , 39 , 40 , 40 , 40 , 40 , 41 , 30 , 30 , 30 , 30 , 30 , 30 , 30 , 30 , 30 , 30 , 30 , 30 , 30 , 30 , 42 , 42 , 42 , 42 , 42 , 43 , 36 , 36 , 36 , 36 , 36 , 36 , 36 , 36 , 44 , 45 , 46 , 46 , 47 , 24 , 24 , 24 , 7 , 7 , 48 , 48 , 48 , 49 , 16 , 50 , 51 , 19 , 52 , 52 , 52 , 52 , 52 , 52 , 52 , 18 , 18 , 18 , 18 , 18 , 18 , 18 , 18 , 53 , 54 , 54 , 55 , 55 , 55

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          Abstract

          Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownas PD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.

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          Most cited references 44

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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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            Mutational heterogeneity in cancer and the search for new cancer genes

            Major international projects are now underway aimed at creating a comprehensive catalog of all genes responsible for the initiation and progression of cancer. These studies involve sequencing of matched tumor–normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here, we describe a fundamental problem with cancer genome studies: as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false positive findings that overshadow true driver events. Here, we show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumor-normal pairs and discover extraordinary variation in (i) mutation frequency and spectrum within cancer types, which shed light on mutational processes and disease etiology, and (ii) mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and allow true cancer genes to rise to attention.
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              Cell migration: integrating signals from front to back.

              Cell migration is a highly integrated multistep process that orchestrates embryonic morphogenesis; contributes to tissue repair and regeneration; and drives disease progression in cancer, mental retardation, atherosclerosis, and arthritis. The migrating cell is highly polarized with complex regulatory pathways that spatially and temporally integrate its component processes. This review describes the mechanisms underlying the major steps of migration and the signaling pathways that regulate them, and outlines recent advances investigating the nature of polarity in migrating cells and the pathways that establish it.
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                Author and article information

                Affiliations
                [1 ]Department of Medical Oncology and the Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA
                [2 ]Institute for Systems Biology, Seattle, Washington 98109, USA
                [3 ]USC Epigenome Center, University of Southern California, Los Angeles, California 90033, USA
                [4 ]University of Southern California, Department of Preventive Medicine, USC/Norris Comprehensive Cancer Center, Los Angeles, California 90033, USA
                [5 ]Computational Biology Center, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
                [6 ]Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
                [7 ]Department of Medicine, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, New York 10021, USA
                [8 ]Canada’s Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 4S6, Canada
                [9 ]The Eli and Edythe L. Broad Institute, Cambridge, Massachusetts 02142, USA
                [10 ]Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
                [11 ]Department of Systems Biology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
                [12 ]Department of Pathology, University of Texas MD Anderson Cancer Center, Texas 77030, USA
                [13 ]Department of Medicine, Harvard Medical School, Boston, Massachusetts 02215, USA
                [14 ]Department of Pathology and Laboratory Medicine, University of North Carolina-Chapel Hill, Chapel Hill, Chapel Hill, North Carolina 27599, USA
                [15 ]Department of Medicine, Vanderbilt University Medical Center, 2215 Garland Avenue, Nashville, Tennessee 37232, USA
                [16 ]Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, 138-736, South Korea
                [17 ]Sir Peter MacCallum Cancer Department of Oncology, University of Melbourne, East Melbourne 3002, Australia
                [18 ]National Cancer Institute, Bethesda, Maryland 20892, USA
                [19 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland 20892, USA
                [20 ]Department of Pathology, Case Western Reserve University, Cleveland, Ohio 44106, USA
                [21 ]Department of Biomolecular Engineering and Center for Biomolecular Science and Engineering, University of California-Santa Cruz, Santa Cruz, California 95064, USA
                [22 ]Division of Gastroenterology, Department of Medicine, Duke University, Durham, North Carolina 27710, USA
                [23 ]Department of Thoracic Surgery, University of Michigan Cancer Center, Ann Arbor, Michigan 48109, USA
                [24 ]University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA
                [25 ]Department of Computer Science & Center for Computational Molecular Biology, Brown University, 115 Waterman Street, Providence, Rhode Island 02912, USA
                [26 ]Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115, USA
                [27 ]National Cancer Center, Goyang, 410-769, Republic of Korea
                [28 ]The Research Institute at Nationwide Children’s Hospital, Columbus, Ohio 43205, USA
                [29 ]The Genome Institute, Washington University, St Louis, Missouri 63108, USA
                [30 ]Greater Poland Cancer Centre, Garbary, 15, 61-866, Poznan, Poland
                [31 ]KU Leuven, Department of Electrical Engineering-ESAT (STADIUS), Leuven, Belgium
                [32 ]Institute for Applied Cancer Science, Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas 77054, USA
                [33 ]The Center for Biomedical Informatics, Harvard Medical School, Boston, Massachusetts 02115, USA
                [34 ]Cancer Biology Division, Johns Hopkins University, Baltimore, Maryland 21231, USA
                [35 ]Helen Diller Family Comprehensive Cancer Center, University of California-San Francisco, San Francisco, California 94143-0128, USA
                [36 ]International Genomics Consortium, Phoenix, Arizona 85004, USA
                [37 ]Buck Institute for Research on Aging, Novato,California 94945, USA
                [38 ]Chonnam National University Medical School, Gwangju, 501-746, Republic of Korea
                [39 ]City Clinical Oncology Dispensary, Saint Petersburg 198255, Russia
                [40 ]Cureline, Inc., South San Francisco, California 94080, USA
                [41 ]Departments of Medicine and Genetics, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA
                [42 ]Helen F. Graham Cancer Center & Research Institute, Christiana Care Health System, Newark, Delaware 19713, USA
                [43 ]Keimyung University School of Medicine, Daegu, 700-712, Republic of Korea
                [44 ]Ontario Tumour Bank – Hamilton site, St. Joseph’s Healthcare Hamilton, Hamilton, Ontario L8N 3Z5, Canada
                [45 ]Ontario Tumour Bank – Kingston site, Kingston General Hospital, Kingston, Ontario K7L 5H6, Canada
                [46 ]Ontario Tumour Bank, Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada
                [47 ]Pusan National University Hospital, Busan, 602–739, Republic of Korea
                [48 ]Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA
                [49 ]Department of Pathology, Duke University, Durham, North Carolina 27710, USA
                [50 ]Department of Surgery, Yonsei University College of Medicine, Seoul, 120–752, Republic of Korea
                [51 ]Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA
                [52 ]SRA International, Fairfax, Virginia 22033, USA
                [53 ]Center for Biomedical Informatics and Information Technology, National Cancer Institute, Rockville, Maryland 20850, USA
                [54 ]National Human Genome Research Institute, Bethesda, Maryland 20892, USA
                [55 ]SAIC-Frederick, Inc., Frederick, Maryland 21702, USA
                Author notes
                Correspondence and requests for materials should be addressed to A.J.B. ( adam_bass@ 123456dfci.harvard.edu )
                Journal
                0410462
                6011
                Nature
                Nature
                Nature
                0028-0836
                1476-4687
                12 September 2014
                23 July 2014
                11 September 2014
                22 September 2014
                : 513
                : 7517
                : 202-209
                NIHMS627842
                10.1038/nature13480
                4170219
                25079317
                ©2014 Macmillan Publishers Limited. All rights reserved

                This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Unported licence. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons licence, users will need to obtain permission from the licence holder to reproduce the material. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-sa/3.0.

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