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      Genome-wide association study identifies multiple risk loci for renal cell carcinoma

      1 , 2 , 2 , 1 , 3 , 4 , 5 , 2 , 2 , 1 , 1 , 2 , 2 , 1 , 2 , 1 , 6 , 7 , 6 , 2 , 1 , 1 , 1 , 8 , 9 , 1 , 8 , 9 , 1 , 2 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 16 , 18 , 19 , 20 , 17 , 21 , 19 , 12 , 22 , 23 , 24 , 25 , 26 , 25 , 26 , 27 , 28 , 29 ,   30 , 31 , 32 , 33 , 34 , 34 , 35 , 36 , 37 , 27 , 35 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 20 , 45 , 45 , 46 , 46 , 29 , 47 , 29 , 47 , 2 , 2 , 2 , 2 , 48 , 2 , 49 , 50 , 51 , 52 , 52 , 53 , 53 , 53 , 54 , 55 , 56 , 55 , 56 , 55 , 56 , 2 , 2 , 2 , 57 , 57 , 57 , 58 , 59 , 59 , 59 , 60 , 60 , 60 , 60 , 61 , 55 , 56 , 55 , 56 , 5 , 2 , 62 , 63 , 64 , 65 , 4 , 66 , 53 , 67 , 2 , 6 , 7 , 1 , 68 , 5 , 69 , 70 , a , 1 , b , 2

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          Abstract

          Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10 −10), 3p22.1 (rs67311347, P=2.5 × 10 −8), 3q26.2 (rs10936602, P=8.8 × 10 −9), 8p21.3 (rs2241261, P=5.8 × 10 −9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10 −8), 11q22.3 (rs74911261, P=2.1 × 10 −10) and 14q24.2 (rs4903064, P=2.2 × 10 −24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.

          Abstract

          Risk for renal cell carcinoma (RCC) is higher when there are first-degree family members with the disease. Here, Scelo and colleagues perform a genome-wide association meta-analysis and new genome-wide scan to identify seven new loci with significant RCC association.

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          Most cited references 24

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          The genetic basis of kidney cancer: a metabolic disease.

          Kidney cancer is not a single disease but comprises a number of different types of cancer that occur in the kidney, each caused by a different gene with a different histology and clinical course that responds differently to therapy. Each of the seven known kidney cancer genes, VHL, MET, FLCN, TSC1, TSC2, FH and SDH, is involved in pathways that respond to metabolic stress or nutrient stimulation. The VHL protein is a component of the oxygen and iron sensing pathway that regulates hypoxia-inducible factor (HIF) levels in the cell. HGF-MET signaling affects the LKB1-AMPK energy sensing cascade. The FLCN-FNIP1-FNIP2 complex binds AMPK and, therefore, might interact with the cellular energy and nutrient sensing pathways AMPK-TSC1/2-mTOR and PI3K-Akt-mTOR. TSC1-TSC2 is downstream of AMPK and negatively regulates mTOR in response to cellular energy deficit. FH and SDH have a central role in the mitochondrial tricarboxylic acid cycle, which is coupled to energy production through oxidative phosphorylation. Mutations in each of these kidney cancer genes result in dysregulation of metabolic pathways involved in oxygen, iron, energy or nutrient sensing, suggesting that kidney cancer is a disease of cell metabolism. Targeting the fundamental metabolic abnormalities in kidney cancer provides a unique opportunity for the development of more-effective forms of therapy for this disease.
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            Comparisons of outcome and prognostic features among histologic subtypes of renal cell carcinoma.

            Our objective was to compare cancer-specific survival and to examine associations with outcome among the histologic subtypes of renal cell carcinoma (RCC). We studied 2385 patients whose first surgery between 1970 and 2000 was a radical nephrectomy for sporadic, unilateral RCC. All RCC tumors were classified following the 1997 Union Internationale Contre le Cancer and American Joint Committee on Cancer guidelines. There were 1985 (83.2%) patients with clear cell, 270 (11.3%) with papillary, 102 (4.3%) with chromophobe, 6 (0.3%) with collecting duct, 5 (0.3%) with purely sarcomatoid RCC and no underlying histologic subtype, and 17 (0.7%) with RCC, not otherwise specified. Cancer-specific survival rates at 5 years for patients with clear cell, papillary, and chromophobe RCC were 68.9%, 87.4%, and 86.7%, respectively. Patients with clear cell RCC had a poorer prognosis compared with patients with papillary and chromophobe RCC (p <0.001). This difference in outcome was observed even after stratifying by 1997 tumor stage and nuclear grade. There was no significant difference in cancer-specific survival between patients with papillary and chromophobe RCC (p = 0.918). The 1997 TNM stage, tumor size, presence of a sarcomatoid component, and nuclear grade were significantly associated with death from clear cell, papillary, and chromophobe RCC. Histologic tumor necrosis was significantly associated with death from clear cell and chromophobe RCC, but not with death from papillary RCC. Our results demonstrate that there are significant differences in outcome and associations with outcome for the different histologic subtypes of RCC, highlighting the need for accurate subtyping.
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              Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33

              Genome-wide association (GWA) studies have thus far identified 10 loci at which common variants influence the risk of developing colorectal cancer (CRC). To enhance power to identify additional loci, we conducted a meta-analysis of three GWA studies from the UK totalling 3,334 cases and 4,628 controls, followed by multiple validation analyses, involving a total of 18,095 CRC cases and 20,197 controls. We identified new associations at 4 CRC risk loci: 1q41 (rs6691170, OR=1.06, P=9.55x10-10; rs6687758, OR=1.09, P=2.27x10-9); 3q26.2 (rs10936599, OR=0.93, P=3.39x10-8); 12q13.13 (rs11169552, OR=0.92, P=1.89x10-10; rs7136702, OR=1.06, P=4.02=x10-8); and 20q13.33 (rs4925386, OR=0.93, P=1.89x10-10). As well as identifying multiple new CRC risk loci this analysis provides evidence that additional CRC-associated variants of similar effect size remain to be discovered.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                09 June 2017
                2017
                : 8
                Affiliations
                [1 ]International Agency for Research on Cancer (IARC) , 69008 Lyon, France
                [2 ]Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department Health and Human Services , Bethesda, Maryland 20892, USA
                [3 ]Department of Computational Biology, St Jude Children's Research Hospital , Memphis, Tennessee 38105, USA
                [4 ]Department of Health Sciences Research, Mayo Clinic , Rochester, Minnesota 55905, USA
                [5 ]Department of Epidemiology, Division of Cancer Prevention and Population Sciences, The University of Texas MD Anderson Cancer Center , Houston, Texas 77230, USA
                [6 ]Centre National de Genotypage, Institut de Genomique, Commissariat à l'Energie Atomique et aux Energies Alternatives , 91057 Evry, France
                [7 ]Fondation Jean Dausset-Centre d'Etude du Polymorphisme Humain , 75010 Paris, France
                [8 ]Center ‘Bioengineering' of the Russian Academy of Sciences , Moscow 117312, Russia
                [9 ]Kurchatov Scientific Center , Moscow 123182, Russia
                [10 ]Institute of Pathology, School of Medicine, University of Belgrade , 11000 Belgrade, Serbia
                [11 ]Clinical Center of Serbia (KCS), Clinic of Urology, University of Belgrade-Faculty of Medicine , 11000 Belgrade, Serbia
                [12 ]Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute , 656 53 Brno, Czech Republic
                [13 ]2nd Faculty of Medicine, Institute of Public Health and Preventive Medicine, Charles University , 150 06 Prague 5, Czech Republic
                [14 ]Department of Preventive Medicine, Faculty of Medicine, Palacky University , 775 15 Olomouc, Czech Republic
                [15 ]National Institute of Public Health , 050463 Bucharest, Romania
                [16 ]Russian N.N. Blokhin Cancer Research Centre , Moscow 115478, Russian Federation
                [17 ]Carol Davila University of Medicine and Pharmacy, Th. Burghele Hospital , 050659 Bucharest, Romania
                [18 ]First Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University , 128 00 Prague 2, Czech Republic
                [19 ]International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University , 70-204 Szczecin, Poland
                [20 ]Regional Authority of Public Health in Banska Bystrica , 975 56 Banska Bystrica, Slovakia
                [21 ]The M Sklodowska-Curie Cancer Center and Institute of Oncology , 02-034 Warsaw, Poland
                [22 ]National Public Health Center, National Directorate of Environmental Health , 1097 Budapest, Hungary
                [23 ]Department of Epidemiology, Institute of Occupational Medicine , 91-348 Lodz, Poland
                [24 ]Université Paris Diderot, INSERM, Unité Variabilité Génétique et Maladies Humaines , 75010 Paris, France
                [25 ]CeRePP, Tenon Hospital , 75020 Paris, France
                [26 ]UPMC Univ Paris 06 GRC n°5 , 75013 Paris, France
                [27 ]Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Université Paris-Saclay, UPS, UVSQ, Gustave Roussy , 94805 Villejuif, France
                [28 ]Department of Epidemiology, German Institute of Human Nutrition (DIfE) Potsdam-Rehbrücke , 14558 Nuthetal, Germany
                [29 ]Department of Public Health and Primary Care, University of Cambridge , Cambridge CB2 0QQ, UK
                [30 ]Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway , 9037 Tromsø, Norway
                [31 ]Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research , 0304 Oslo, Norway
                [32 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet , 171 77 Stockholm, Sweden
                [33 ]Genetic Epidemiology Group, Folkhälsan Research Center , 00250 Helsinki, Finland
                [34 ]Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University , 901 85 Umeå, Sweden
                [35 ]Cancer Epidemiology Centre, Cancer Council Victoria , Melbourne, Victoria 3004, Australia
                [36 ]QIMR Berghofer Medical Research Institute , Herston, Queensland 4006, Australia
                [37 ]School of Public Health, The University of Queensland , Brisbane, Queensland 4072, Australia
                [38 ]Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne , Carlton, Victoria 3053, Australia
                [39 ]Human Genetics Foundation (HuGeF) , 10126 Torino, Italy
                [40 ]Department of Medicine, The University of Melbourne , Melbourne, Victoria 3010, Australia
                [41 ]Genetic Medicine and Family Cancer Clinic, Royal Melbourne Hospital , Parkville, Victoria 3050, Australia
                [42 ]HUNT Research Centre, Department of Public Health and General Practice, Norwegian University of Science and Technology , Levanger 7600, Norway
                [43 ]Department of Public Health and General Practice, Faculty of Medicine, Norwegian University of Science and Technology , Trondheim 7491, Norway
                [44 ]London School of Hygiene and Tropical Medicine, University of London , London WC1H 9SH, UK
                [45 ]Institute of Environmental Medicine, Karolinska Institutet , 171 77 Stockholm, Sweden
                [46 ]Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital , Leeds LS9 7TF, UK
                [47 ]Department of Oncology, University of Cambridge , Cambridge CB1 8RN, UK
                [48 ]Department of Health, National Institute for Health and Welfare , 00271 Helsinki, Finland
                [49 ]Vanderbilt-Ingram Cancer Center, Department of Urology, Vanderbilt University Medical Center , Nashville, Tennessee 37232, USA
                [50 ]Vanderbilt-Ingram Cancer Center, Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt Genetics Institute, Vanderbilt University Medical Center , Nashville, Tennessee 37209, USA
                [51 ]Vanderbilt-Ingram Cancer Center, Division of Epidemiology, Department of Medicine, Institute for Medicine and Public Health, Vanderbilt University Medical Center , Nashville, Tennessee 37203, USA
                [52 ]American Cancer Society , Atlanta, Georgia 30303, USA
                [53 ]Dana-Farber Cancer Institute , Boston, Massachusetts 02215, USA
                [54 ]Warren Alpert Medical School of Brown University , Providence, Rhode Island 02903, USA
                [55 ]Harvard T.H. Chan School of Public Health , Boston, Massachusetts 02115, USA
                [56 ]Brigham and Women's Hospital and VA Boston , Boston, Massachusetts 02115, USA
                [57 ]Division of Urology, Spectrum Health , Grand Rapids, Michigan 49503, USA
                [58 ]College of Human Medicine, Michigan State University , Grand Rapids, Michigan 49503, USA
                [59 ]Van Andel Research Institute, Center for Cancer Genomics and Quantitative Biology , Grand Rapids, Michigan 49503, USA
                [60 ]Cancer Prevention Program, Fred Hutchinson Cancer Research Center , Seattle, Washington 98109, USA
                [61 ]Department of Epidemiology and Biostatistics, School of Public Health Indiana University Bloomington , Bloomington, Indiana 47405, USA
                [62 ]Department of Urology, The University of Texas M.D. Anderson Cancer Center , Houston, Texas 77030, USA
                [63 ]Department of Oncology, Cambridge University Hospitals NHS Foundation Trust , Cambridge CB2 0QQ, UK
                [64 ]Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai , New York, New York 10029, USA
                [65 ]Medical Oncology, Royal Marsden NHS Foundation Trust , London SW3 6JJ, UK
                [66 ]Department of Urology, Mayo Medical School and Mayo Clinic , Rochester, Minnesota 55902, USA
                [67 ]McGill University and Genome Quebec Innovation Centre , Montreal, Quebec, Canada H3A 0G1
                [68 ]Department of Health Sciences Research, Mayo Clinic , Jacksonville, Florida 32224, USA
                [69 ]Division of Genetics and Epidemiology, The Institute of Cancer Research , London SW7 3RP, UK
                [70 ]Division of Molecular Pathology, The Institute of Cancer Research , London SW7 3RP, UK
                Author notes
                [*]

                These authors contributed equally to this work.

                [†]

                These authors jointly supervised this work.

                Article
                ncomms15724
                10.1038/ncomms15724
                5472706
                28598434
                Copyright © 2017, The Author(s)

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

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