Recent genomic studies of sporadic clear cell renal cell carcinoma (ccRCC) have uncovered novel driver genes and pathways. Given the unequal incidence rates among men and women (male:female incidence ratio approaches 2:1), we compared the genome-wide distribution of the chromosomal abnormalities in both sexes. We observed a higher frequency for the somatic recurrent chromosomal copy number variations (CNVs) of autosomes in male subjects, whereas somatic loss of chromosome X was detected exclusively in female patients (17.1%). Furthermore, somatic loss of chromosome Y (LOY) was detected in about 40% of male subjects, while mosaic LOY was detected in DNA isolated from peripheral blood in 9.6% of them, and was the only recurrent CNV in constitutional DNA samples. LOY in constitutional DNA, but not in tumor DNA was associated with older age. Amongst Y-linked genes that were downregulated due to LOY, KDM5D and KDM6C epigenetic modifiers have functionally-similar X-linked homologs whose deficiency is involved in ccRCC progression. Our findings establish somatic LOY as a highly recurrent genetic defect in ccRCC that leads to downregulation of hitherto unsuspected epigenetic factors, and suggest that different mechanisms may underlie the somatic and mosaic LOY observed in tumors and peripheral blood, respectively.

1st Faculty of Medicine Institute of Hygiene and Epidemiology Charles University Prague Studničkova 7 Praha 2 128 00 Prague Czech Republic

Carol Davila University of Medicine and Pharmacy Th Burghele Hospital 20 Panduri Street 050659 Bucharest Romania

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute and MF MU Zluty Kopec 7 656 53 Brno Czech Republic

Department of Human Genetics McGill University 1205 Dr Penfield Avenue Montreal QC H3A 1B1 Canada

Department of Preventive Medicine Faculty of Medicine Palacky University Hnevotinska 3 775 15 Olomouc Czech Republic

European Molecular Biology Laboratory European Bioinformatics Institute EMBL EBI Wellcome Trust Genome Campus Hinxton CB10 1SD UK

International Agency for Research on Cancer 150 cours Albert Thomas 69008 Lyon France

Karolinska Institutet Department of Pathology SE 171 77 Stockholm Sweden

Laboratory for Epigenetics and Environment Centre National de Génotypage CEA Institut de Génomique 2 rue Gaston Crémieux 91000 Evry France

Leeds Institute of Cancer and Pathology University of Leeds Cancer Research Building St James's University Hospital Leeds LS9 7TF UK

McGill University and Genome Quebec Innovation Centre 740 Doctor Penfield Avenue Montreal QC H3A 0G1 Canada

National Institute of Public Health Dr Leonte Anastasievici 1 3 sector 5 Bucuresti 050463 Romania

Russian N N Blokhin Cancer Research Centre Kashirskoye shosse 24 Moscow 115478 Russian Federation

University Hospital Motol 5 Úvalu 84 150 06 Prague Czech Republic

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