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      Influence of common genetic variation on lung cancer risk: meta-analysis of 14 900 cases and 29 485 controls

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      1 , 2 , 3 , 4 , 5 , 6 , 7 , 41 , 1 , 8 , 9 , 1 , 2 , 2 , 10 , 11 , 11 , 12 , 13 , 14 , 15 , 6 , 16 , 16 , 16 , 18 , 17 , 17 , 4 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 28 , 29 , 30 , 31 , 32 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 37 , 5 , 5 , 5 , 5 , 39 , 41 , 40 , 41 , 3 , 9 , 3 , 1 , 16 , 42 , * , 8 , 11 , for TRICL Research Team
      Human Molecular Genetics
      Oxford University Press

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          Abstract

          Recent genome-wide association studies (GWASs) have identified common genetic variants at 5p15.33, 6p21–6p22 and 15q25.1 associated with lung cancer risk. Several other genetic regions including variants of CHEK2 (22q12), TP53BP1 (15q15) and RAD52 (12p13) have been demonstrated to influence lung cancer risk in candidate- or pathway-based analyses. To identify novel risk variants for lung cancer, we performed a meta-analysis of 16 GWASs, totaling 14 900 cases and 29 485 controls of European descent. Our data provided increased support for previously identified risk loci at 5p15 ( P = 7.2 × 10 −16), 6p21 ( P = 2.3 × 10 −14) and 15q25 ( P = 2.2 × 10 −63). Furthermore, we demonstrated histology-specific effects for 5p15, 6p21 and 12p13 loci but not for the 15q25 region. Subgroup analysis also identified a novel disease locus for squamous cell carcinoma at 9p21 ( CDKN2A/p16 INK4A/p14 ARF/CDKN2B/p15 INK4B / ANRIL; rs1333040, P = 3.0 × 10 −7) which was replicated in a series of 5415 Han Chinese ( P = 0.03; combined analysis, P = 2.3 × 10 −8). This large analysis provides additional evidence for the role of inherited genetic susceptibility to lung cancer and insight into biological differences in the development of the different histological types of lung cancer.

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          Most cited references77

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          Twelve type 2 diabetes susceptibility loci identified through large-scale association analysis.

          By combining genome-wide association data from 8,130 individuals with type 2 diabetes (T2D) and 38,987 controls of European descent and following up previously unidentified meta-analysis signals in a further 34,412 cases and 59,925 controls, we identified 12 new T2D association signals with combined P<5x10(-8). These include a second independent signal at the KCNQ1 locus; the first report, to our knowledge, of an X-chromosomal association (near DUSP9); and a further instance of overlap between loci implicated in monogenic and multifactorial forms of diabetes (at HNF1A). The identified loci affect both beta-cell function and insulin action, and, overall, T2D association signals show evidence of enrichment for genes involved in cell cycle regulation. We also show that a high proportion of T2D susceptibility loci harbor independent association signals influencing apparently unrelated complex traits.
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            DNA double-strand breaks: signaling, repair and the cancer connection.

            To ensure the high-fidelity transmission of genetic information, cells have evolved mechanisms to monitor genome integrity. Cells respond to DNA damage by activating a complex DNA-damage-response pathway that includes cell-cycle arrest, the transcriptional and post-transcriptional activation of a subset of genes including those associated with DNA repair, and, under some circumstances, the triggering of programmed cell death. An inability to respond properly to, or to repair, DNA damage leads to genetic instability, which in turn may enhance the rate of cancer development. Indeed, it is becoming increasingly clear that deficiencies in DNA-damage signaling and repair pathways are fundamental to the etiology of most, if not all, human cancers. Here we describe recent progress in our understanding of how cells detect and signal the presence and repair of one particularly important form of DNA damage induced by ionizing radiation-the DNA double-strand break (DSB). Moreover, we discuss how tumor suppressor proteins such as p53, ATM, Brca1 and Brca2 have been linked to such pathways, and how accumulating evidence is connecting deficiencies in cellular responses to DNA DSBs with tumorigenesis.
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              Long non-coding RNA ANRIL is required for the PRC2 recruitment to and silencing of p15(INK4B) tumor suppressor gene.

              A 42 kb region on human chromosome 9p21 encodes for three distinct tumor suppressors, p16(INK4A), p14(ARF) and p15(INK4B), and is altered in an estimated 30-40% of human tumors. The expression of the INK4A-ARF-INK4B gene cluster is silenced by polycomb during normal cell growth and is activated by oncogenic insults and during aging. How the polycomb is recruited to repress this gene cluster is unclear. Here, we show that expression of oncogenic Ras, which stimulates the expression of p15(INK4B) and p16(INK4A), but not p14(ARF), inhibits the expression of ANRIL (antisense non-coding RNA in the INK4 locus), a 3.8 kb-long non-coding RNA expressed in the opposite direction from INK4A-ARF-INK4B. We show that the p15(INK4B) locus is bound by SUZ12, a component of polycomb repression complex 2 (PRC2), and is H3K27-trimethylated. Notably, depletion of ANRIL disrupts the SUZ12 binding to the p15(INK4B) locus, increases the expression of p15(INK4B), but not p16(INK4A) or p14(ARF), and inhibits cellular proliferation. Finally, RNA immunoprecipitation demonstrates that ANRIL binds to SUZ12 in vivo. Collectively, these results suggest a model in which ANRIL binds to and recruits PRC2 to repress the expression of p15(INK4B) locus.
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                Author and article information

                Journal
                Hum Mol Genet
                Hum. Mol. Genet
                hmg
                hmg
                Human Molecular Genetics
                Oxford University Press
                0964-6906
                1460-2083
                15 November 2012
                16 August 2012
                16 August 2012
                : 21
                : 22
                : 4980-4995
                Affiliations
                [1 ]International Agency for Research on Cancer , Lyon69008, France,
                [2 ]Samuel Lunenfeld Research Institute of Mount Sinai Hospital , Toronto, ON, CanadaM5G 1X5,
                [3 ]DeCODE Genetics , Reykjavik, Iceland,
                [4 ]Harvard University School of Public Health , Boston, MA 02115, USA,
                [5 ]Roy Castle Lung Cancer Research Programme,Department of Molecular and Clinical Cancer Medicine, The University of Liverpool Cancer Research Centre, Institute of Translational Medicine, The University of Liverpool , Liverpool, UK,
                [6 ]Department of Genetic Epidemiology, University Medical Center , Georg-August-University Göttingen , 37073 Göttingen, Germany,
                [7 ]DKFZ - German Cancer Research Center , Translational Lung Research Centre Heidelberg (TLRC-H) , Member of the German Center for Lung Research , 69120 Heidelberg, Germany,
                [8 ]Division of Genetics and Epidemiology, Institute of Cancer Research , Sutton, Surrey SM2 5NG, UK,
                [9 ]Department of Epidemiology and Biostatistics, School of Public Health, Nanjing Medical University , Nanjing, China,
                [10 ]Women's College Research Institute , Toronto, Ontario, Canada,
                [11 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, U.S. Public Health Service , Bethesda, MD 20892, USA,
                [12 ]American Cancer Society, Epidemiology and Surveillance Research , Atlanta, GA 30301, USA,
                [13 ]Department of Oncology, Cambridge University Hospitals NHS Foundation Trust , Cambridge, UK,
                [14 ]Helmholtz Center Munich, Institute of Epidemiology I , 85764 Neuherberg, Germany,
                [15 ]Chair of Epidemiology, Institute of Medical Informatics, Biometry and Epidemiology, Ludwig-Maximilians-Universität Munich , 81377 Munich, Germany,
                [16 ]Department of Genetics and
                [17 ]Department of Epidemiology, The University of Texas MD Anderson Cancer Center , Houston, TX 77030, USA,
                [18 ]Baylor College of Medicine , Houston, TX 77030, USA,
                [19 ]Institute of Carcinogenesis, Russian N.N. Blokhin Cancer Research Centre , 115478 Moscow, Russia,
                [20 ]Department of Epidemiology, Institute of Occupational Medicine , 91348 Lodz, Poland,
                [21 ]The M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology , Warsaw 02781, Poland,
                [22 ]National Institute of Environmental Health , Budapest 1097, Hungary,
                [23 ]Regional Authority of Public Health , Banská Bystrica 97556, Slovak Republic,
                [24 ]National Institute of Public Health , Bucharest 050463, Romania,
                [25 ]1st Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University in Prague , 128 00 Prague 2, Czech Republic,
                [26 ]Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute , Brno 65653, Czech Republic,
                [27 ]Palacky University , Olomouc 77515, Czech Republic,
                [28 ]Department of Cancer Research and Molecular Medicine, Faculty of Medicine, Norwegian University of Science and Technology , Trondheim 7489, Norway,
                [29 ]Department of Laboratory Medicine, Children's and Women's Health, Faculty of Medicine and
                [30 ]Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology, Trondheim 7489, Norway
                [31 ]Department of Community Medicine, University of Tromso , Tromso9037, Norway,
                [32 ]Fred Hutchinson Cancer Research Center , Seattle, WA 98109, USA,
                [33 ]Centre d'Etude du Polymorphisme Humain (CEPH) , Paris75010, France,
                [34 ]INSERM U946 , Paris 75010, France,
                [35 ]Institute of Molecular and Cell Biology, University of Tartu , Tartu 51010, Estonia,
                [36 ]Competence Centre on Reproductive Medicine and Biology , 50410 Tartu, Estonia,
                [37 ]Estonian Genome Center, Institute of Molecular and Cell Biology , Tartu 51010, Estonia,
                [38 ]Department of Genetic Medicine and Development, University of Geneva Medical School , Geneva, Switzerland,
                [39 ]Translational Research Unit and
                [40 ]Department of Thoracic Surgery , Thoraxklinik am Universitätsklinikum Heidelberg, Germany ,
                [41 ]Translational Lung Research Centre Heidelberg (TLRC-H) , Member of the German Center for Lung Research , 69126 Heidelberg, Germany and
                [42 ]Department of Community and Family Medicine , Geisel School of Medicine , Dartmouth College, Hanover, NH 03750, USA
                Author notes
                [* ]To whom correspondence should be addressed at: Department of Community and Family Medicine, Geisel School of Medicine, Dartmouth College, 46 Centerra Parkway Suite 330, Lebanon, NH 03766. Tel: +603-653-6696; Email: Christopher.I.Amos@ 123456Dartmouth.edu
                [†]

                These authors contributed equally to this work.

                [‡]

                Transdisciplinary Research in Cancer of the Lung.

                Article
                dds334
                10.1093/hmg/dds334
                3607485
                22899653
                4cddc709-b9a7-44ec-a11f-5c29acf79539
                © The Author 2012. Published by Oxford University Press.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/2.5), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 4 May 2012
                : 23 July 2012
                : 1 August 2012
                Categories
                Association Studies Articles

                Genetics
                Genetics

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