Comprehensive molecular characterization of gastric adenocarcinoma

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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 24

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Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis.

Ronglai Shen, Adam B. Olshen, Marc Ladanyi (2009)

The molecular complexity of a tumor manifests itself at the genomic, epigenomic, transcriptomic and proteomic levels. Genomic profiling at these multiple levels should allow an integrated characterization of tumor etiology. However, there is a shortage of effective statistical and bioinformatic tools for truly integrative data analysis. The standard approach to integrative clustering is separate clustering followed by manual integration. A more statistically powerful approach would incorporate all data types simultaneously and generate a single integrated cluster assignment. We developed a joint latent variable model for integrative clustering. We call the resulting methodology iCluster. iCluster incorporates flexible modeling of the associations between different data types and the variance-covariance structure within data types in a single framework, while simultaneously reducing the dimensionality of the datasets. Likelihood-based inference is obtained through the Expectation-Maximization algorithm. We demonstrate the iCluster algorithm using two examples of joint analysis of copy number and gene expression data, one from breast cancer and one from lung cancer. In both cases, we identified subtypes characterized by concordant DNA copy number changes and gene expression as well as unique profiles specific to one or the other in a completely automated fashion. In addition, the algorithm discovers potentially novel subtypes by combining weak yet consistent alteration patterns across data types. R code to implement iCluster can be downloaded at http://www.mskcc.org/mskcc/html/85130.cfm

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Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy.

Michael Green, Scott J. Rodig, Przemyslaw Juszczynski … (2012)

Programmed cell death ligand 1 (PD-L1) is a molecule expressed on antigen-presenting cells that engages the PD-1 receptor on T cells and inhibits T-cell receptor signaling. The PD-1 axis can be exploited by tumor cells to dampen host antitumor immune responses and foster tumor cell survival. PD-1 blockade has shown promise in multiple malignancies but should be directed toward patients in whom it will be most effective. In recent studies, we found that the chromosome 9p24.1 amplification increased the gene dosage of PD-L1 and its induction by JAK2 in a subset of patients with classical Hodgkin lymphoma (cHL). However, cHLs with normal 9p24.1 copy numbers also expressed detectable PD-L1, prompting analyses of additional PD-L1 regulatory mechanisms. Herein, we utilized immunohistochemical, genomic, and functional analyses to define alternative mechanisms of PD-L1 activation in cHL and additional EBV(+) lymphoproliferative disorders. We identified an AP-1-responsive enhancer in the PD-L1 gene. In cHL Reed-Sternberg cells, which exhibit constitutive AP-1 activation, the PD-L1 enhancer binds AP-1 components and increases PD-L1 promoter activity. In addition, we defined Epstein-Barr virus (EBV) infection as an alternative mechanism for PD-L1 induction in cHLs with diploid 9p24.1. PD-L1 was also expressed by EBV-transformed lymphoblastoid cell lines as a result of latent membrane protein 1-mediated, JAK/STAT-dependent promoter and AP-1-associated enhancer activity. In addition, more than 70% of EBV(+) posttransplant lymphoproliferative disorders expressed detectable PD-L1. AP-1 signaling and EBV infection represent alternative mechanisms of PD-L1 induction and extend the spectrum of tumors in which to consider PD-1 blockade.

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Recent patterns in gastric cancer: a global overview.

Paola Bertuccio, Liliane Chatenoud, Fabio Levi … (2009)

Until the mid-1990s, gastric cancer has been the first cause of cancer death worldwide, although rates had been declining for several decades and gastric cancer has become a relatively rare cancer in North America and in most Northern and Western Europe, but not in Eastern Europe, Russia and selected areas of Central and South America or East Asia. We analyzed gastric cancer mortality in Europe and other areas of the world from 1980 to 2005 using joinpoint regression analysis, and provided updated site-specific incidence rates from 51 selected registries. Over the last decade, the annual percent change (APC) in mortality rate was around -3, -4% for the major European countries. The APC were similar for the Republic of Korea (APC = -4.3%), Australia (-3.7%), the USA (-3.6%), Japan (-3.5%), Ukraine (-3%) and the Russian Federation (-2.8%). In Latin America, the decline was less marked, but constant with APC around -1.6% in Chile and Brazil, -2.3% in Argentina and Mexico and -2.6% in Colombia. Cancers in the fundus and pylorus are more common in high incidence and mortality areas and have been declining more than cardia gastric cancer. Steady downward trends persist in gastric cancer mortality worldwide even in middle aged population, and hence further appreciable declines are likely in the near future.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 12 September 2014

Publication date (Electronic): 23 July 2014

Publication date (Print): 11 September 2014

Publication date PMC-release: 22 September 2014

Volume: 513

Issue: 7517

Pages: 202-209

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 )

Article

Manuscript ID: NIHMS627842

DOI: 10.1038/nature13480

PMC ID: 4170219

PubMed ID: 25079317

SO-VID: c70ab42f-f302-403e-b5e6-ce197e109ea3

License:

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.

Comprehensive molecular characterization of gastric adenocarcinoma

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Most cited references 24

Integrative clustering of multiple genomic data types using a joint latent variable model with application to breast and lung cancer subtype analysis.

Constitutive AP-1 activity and EBV infection induce PD-L1 in Hodgkin lymphomas and posttransplant lymphoproliferative disorders: implications for targeted therapy.

Recent patterns in gastric cancer: a global overview.

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