title: Variation in genomic landscape of clear cell renal cell carcinoma across Europe.
abstract: The incidence of renal cell carcinoma (RCC) is increasing worldwide, and its prevalence is particularly high in some parts of Central Europe. Here we undertake whole-genome and transcriptome sequencing of clear cell RCC (ccRCC), the most common form of the disease, in patients from four different European countries with contrasting disease incidence to explore the underlying genomic architecture of RCC. Our findings support previous reports on frequent aberrations in the epigenetic machinery and PI3K/mTOR signalling, and uncover novel pathways and genes affected by recurrent mutations and abnormal transcriptome patterns including focal adhesion, components of extracellular matrix (ECM) and genes encoding FAT cadherins. Furthermore, a large majority of patients from Romania have an unexpected high frequency of A:T>T:A transversions, consistent with exposure to aristolochic acid (AA). These results show that the processes underlying ccRCC tumorigenesis may vary in different populations and suggest that AA may be an important ccRCC carcinogen in Romania, a finding with major public health implications.
authors.affiliation: International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Scelo
authors.affiliation: 1] Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, Quebec, Canada H3A 1B1 [2] McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, Quebec, Canada H3A 0G1.
authors.forename: Yasser
authors.initials: Y
authors.lastname: Riazalhosseini
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
authors.forename: Liliana
authors.initials: L
authors.lastname: Greger
authors.affiliation: McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, Quebec, Canada H3A 0G1.
authors.forename: Louis
authors.initials: L
authors.lastname: Letourneau
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
authors.forename: Mar
authors.initials: M
authors.lastname: Gonzàlez-Porta
authors.affiliation: International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
authors.forename: Magdalena B
authors.initials: MB
authors.lastname: Wozniak
authors.affiliation: McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, Quebec, Canada H3A 0G1.
authors.forename: Mathieu
authors.initials: M
authors.lastname: Bourgey
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Patricia
authors.initials: P
authors.lastname: Harnden
authors.affiliation: Department of Pathology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Egevad
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Sharon M
authors.initials: SM
authors.lastname: Jackson
authors.affiliation: 1] Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, Quebec, Canada H3A 1B1 [2] McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, Quebec, Canada H3A 0G1.
authors.forename: Mehran
authors.initials: M
authors.lastname: Karimzadeh
authors.affiliation: 1] Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, Quebec, Canada H3A 1B1 [2] McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, Quebec, Canada H3A 0G1.
authors.forename: Madeleine
authors.initials: M
authors.lastname: Arseneault
authors.affiliation: McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, Quebec, Canada H3A 0G1.
authors.forename: Pierre
authors.initials: P
authors.lastname: Lepage
authors.affiliation: Fondation Jean Dausset - Centre d'Etude du Polymorphisme Humain, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: How-Kit
authors.affiliation: Fondation Jean Dausset - Centre d'Etude du Polymorphisme Humain, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Antoine
authors.initials: A
authors.lastname: Daunay
authors.affiliation: Fondation Jean Dausset - Centre d'Etude du Polymorphisme Humain, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Victor
authors.initials: V
authors.lastname: Renault
authors.affiliation: Fondation Jean Dausset - Centre d'Etude du Polymorphisme Humain, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Blanché
authors.affiliation: Fondation Jean Dausset - Centre d'Etude du Polymorphisme Humain, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Tubacher
authors.affiliation: Fondation Jean Dausset - Centre d'Etude du Polymorphisme Humain, 27 rue Juliette Dodu, 75010 Paris, France.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Sehmoun
authors.affiliation: Institute of Mathematics and Computer Science, University of Latvia, 29 Rainis Boulevard, Riga LV-1459, Latvia.
authors.forename: Juris
authors.initials: J
authors.lastname: Viksna
authors.affiliation: Institute of Mathematics and Computer Science, University of Latvia, 29 Rainis Boulevard, Riga LV-1459, Latvia.
authors.forename: Edgars
authors.initials: E
authors.lastname: Celms
authors.affiliation: Institute of Mathematics and Computer Science, University of Latvia, 29 Rainis Boulevard, Riga LV-1459, Latvia.
authors.forename: Martins
authors.initials: M
authors.lastname: Opmanis
authors.affiliation: Institute of Mathematics and Computer Science, University of Latvia, 29 Rainis Boulevard, Riga LV-1459, Latvia.
authors.forename: Andris
authors.initials: A
authors.lastname: Zarins
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Naveen S
authors.initials: NS
authors.lastname: Vasudev
authors.affiliation: Department of Pathology, The Beatson Institute for Cancer Research, Switchback Road, Bearsden, Glasgow G61 1BD, UK.
authors.forename: Morag
authors.initials: M
authors.lastname: Seywright
authors.affiliation: International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
authors.forename: Behnoush
authors.initials: B
authors.lastname: Abedi-Ardekani
authors.affiliation: International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
authors.forename: Christine
authors.initials: C
authors.lastname: Carreira
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Selby
authors.affiliation: Leeds Teaching Hospitals NHS Trust, Pyrah Department of Urology, Lincoln Wing, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Jon J
authors.initials: JJ
authors.lastname: Cartledge
authors.affiliation: International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
authors.forename: Graham
authors.initials: G
authors.lastname: Byrnes
authors.affiliation: International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
authors.forename: Jiri
authors.initials: J
authors.lastname: Zavadil
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
authors.forename: Jing
authors.initials: J
authors.lastname: Su
authors.affiliation: First Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University in Prague, Studničkova 7, Praha 2, 128 00 Prague, Czech Republic.
authors.forename: Ivana
authors.initials: I
authors.lastname: Holcatova
authors.affiliation: University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech Republic.
authors.forename: Antonin
authors.initials: A
authors.lastname: Brisuda
authors.affiliation: Russian N.N. Blokhin Cancer Research Centre, Kashirskoye shosse 24, Moscow 115478, Russian Federation.
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.affiliation: Russian N.N. Blokhin Cancer Research Centre, Kashirskoye shosse 24, Moscow 115478, Russian Federation.
authors.forename: Anush
authors.initials: A
authors.lastname: Moukeria
authors.affiliation: Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Zluty Kopec 7, 656 53 Brno, Czech Republic.
authors.forename: Lenka
authors.initials: L
authors.lastname: Foretova
authors.affiliation: Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Zluty Kopec 7, 656 53 Brno, Czech Republic.
authors.forename: Marie
authors.initials: M
authors.lastname: Navratilova
authors.affiliation: National Institute of Public Health, Dr Leonte Anastasievici 1-3, sector 5, Bucuresti 050463, Romania.
authors.forename: Dana
authors.initials: D
authors.lastname: Mates
authors.affiliation: Carol Davila University of Medicine and Pharmacy, Th. Burghele Hospital, 20 Panduri Street, 050659 Bucharest, Romania.
authors.forename: Viorel
authors.initials: V
authors.lastname: Jinga
authors.affiliation: Centre 'Bioengineering', The Russian Academy of Sciences, Moscow 117312, Russian Federation.
authors.forename: Artem
authors.initials: A
authors.lastname: Artemov
authors.affiliation: National Research Centre 'Kurchatov Institute', 1 Akademika Kurchatova pl., Moscow 123182, Russia.
authors.forename: Artem
authors.initials: A
authors.lastname: Nedoluzhko
authors.affiliation: Centre 'Bioengineering', The Russian Academy of Sciences, Moscow 117312, Russian Federation.
authors.forename: Alexander
authors.initials: A
authors.lastname: Mazur
authors.affiliation: National Research Centre 'Kurchatov Institute', 1 Akademika Kurchatova pl., Moscow 123182, Russia.
authors.forename: Sergey
authors.initials: S
authors.lastname: Rastorguev
authors.affiliation: National Research Centre 'Kurchatov Institute', 1 Akademika Kurchatova pl., Moscow 123182, Russia.
authors.forename: Eugenia
authors.initials: E
authors.lastname: Boulygina
authors.affiliation: Centro Nacional de Análisis Genómico, Baldiri Reixac, 4, Barcleona Science Park - Tower I, 08028 Barcelona, Spain.
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.affiliation: Centro Nacional de Análisis Genómico, Baldiri Reixac, 4, Barcleona Science Park - Tower I, 08028 Barcelona, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Gut
authors.affiliation: Centre National de Génotypage, CEA - Institute de Génomique, 2 rue Gaston Crémieux, 91000 Evry, France.
authors.forename: Marie-Therese
authors.initials: MT
authors.lastname: Bihoreau
authors.affiliation: Centre National de Génotypage, CEA - Institute de Génomique, 2 rue Gaston Crémieux, 91000 Evry, France.
authors.forename: Doris
authors.initials: D
authors.lastname: Lechner
authors.affiliation: Centre National de Génotypage, CEA - Institute de Génomique, 2 rue Gaston Crémieux, 91000 Evry, France.
authors.forename: Mario
authors.initials: M
authors.lastname: Foglio
authors.affiliation: Centro Nacional de Análisis Genómico, Baldiri Reixac, 4, Barcleona Science Park - Tower I, 08028 Barcelona, Spain.
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.affiliation: 1] Centre 'Bioengineering', The Russian Academy of Sciences, Moscow 117312, Russian Federation [2] National Research Centre 'Kurchatov Institute', 1 Akademika Kurchatova pl., Moscow 123182, Russia.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Skryabin
authors.affiliation: 1] Centre 'Bioengineering', The Russian Academy of Sciences, Moscow 117312, Russian Federation [2] National Research Centre 'Kurchatov Institute', 1 Akademika Kurchatova pl., Moscow 123182, Russia.
authors.forename: Egor
authors.initials: E
authors.lastname: Prokhortchouk
authors.affiliation: Faculty of Medicine, Institut National de la Santé et de la Recherche Medicale (INSERM) and University Toulouse III-Paul Sabatier, UMR 1027, 37 allées Jules Guesde, 31000 Toulouse, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Cambon-Thomsen
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
authors.forename: Johan
authors.initials: J
authors.lastname: Rung
authors.affiliation: 1] Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, Quebec, Canada H3A 1B1 [2] McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, Quebec, Canada H3A 0G1.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Bourque
authors.affiliation: International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.affiliation: Centre National de Génotypage, CEA - Institute de Génomique, 2 rue Gaston Crémieux, 91000 Evry, France.
authors.forename: Jörg
authors.initials: J
authors.lastname: Tost
authors.affiliation: Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds LS9 7TF, UK.
authors.forename: Rosamonde E
authors.initials: RE
authors.lastname: Banks
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton CB10 1SD, UK.
authors.forename: Alvis
authors.initials: A
authors.lastname: Brazma
authors.affiliation: 1] Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, Quebec, Canada H3A 1B1 [2] Fondation Jean Dausset - Centre d'Etude du Polymorphisme Humain, 27 rue Juliette Dodu, 75010 Paris, France [3] Centre National de Génotypage, CEA - Institute de Génomique, 2 rue Gaston Crémieux, 91000 Evry, France.
authors.forename: G Mark
authors.initials: GM
authors.lastname: Lathrop
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D015331:Cohort Studies; D005060:Europe; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D014644:Genetic Variation; D015894:Genome, Human / Q000235:genetics*; D023281:Genomics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D059645:Mutation Rate; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D012326:RNA Splicing / Q000235:genetics; D017422:Sequence Analysis, DNA; D015398:Signal Transduction / Q000235:genetics
chemical_list: D015514:Oncogene Proteins, Fusion; D019869:Phosphatidylinositol 3-Kinases