Loss of chromosome Y leads to down regulation of KDM5D and KDM6C epigenetic modifiers in clear cell renal cell carcinoma.
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.
Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.|McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
Madeleine
M
Arseneault
Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.|McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
Jean
J
Monlong
Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds, LS9 7TF, UK.
Naveen S
NS
Vasudev
International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
Ruhina S
RS
Laskar
Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.|McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
Maryam
M
Safisamghabadi
Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds, LS9 7TF, UK.
Patricia
P
Harnden
Karolinska Institutet, Department of Pathology, SE-171 77 Stockholm, Sweden.
Lars
L
Egevad
Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.|McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
Nazanin
N
Nourbehesht
Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.|McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
Pudchalaluck
P
Panichnantakul
First Faculty of Medicine, Institute of Hygiene and Epidemiology, Charles University in Prague, Studničkova 7, Praha 2, 128 00 Prague, Czech Republic.
Ivana
I
Holcatova
University Hospital Motol, V Úvalu 84, 150 06 Prague, Czech Republic.
Antonin
A
Brisuda
Department of Preventive Medicine, Faculty of Medicine, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
Vladimir
V
Janout
Department of Preventive Medicine, Faculty of Medicine, Palacky University, Hnevotinska 3, 775 15 Olomouc, Czech Republic.
Helena
H
Kollarova
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Zluty Kopec 7, 656 53 Brno, Czech Republic.
Lenka
L
Foretova
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and MF MU, Zluty Kopec 7, 656 53 Brno, Czech Republic.
Marie
M
Navratilova
National Institute of Public Health, Dr Leonte Anastasievici 1-3, sector 5, Bucuresti 050463, Romania.
Dana
D
Mates
Carol Davila University of Medicine and Pharmacy, Th. Burghele Hospital, 20 Panduri Street, 050659 Bucharest, Romania.
Viorel
V
Jinga
Russian N.N. Blokhin Cancer Research Centre, Kashirskoye shosse 24, Moscow 115478, Russian Federation.
David
D
Zaridze
Russian N.N. Blokhin Cancer Research Centre, Kashirskoye shosse 24, Moscow 115478, Russian Federation.
Anush
A
Mukeria
Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.|McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
Pouria
P
Jandaghi
International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
Paul
P
Brennan
European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Trust Genome Campus, Hinxton, CB10 1SD, UK.
Alvis
A
Brazma
Laboratory for Epigenetics &Environment, Centre National de Génotypage, CEA-Institut de Génomique, 2 rue Gaston Crémieux, 91000 Evry, France.
Jorg
J
Tost
International Agency for Research on Cancer (IARC), 150 cours Albert Thomas, 69008 Lyon, France.
Ghislaine
G
Scelo
Leeds Institute of Cancer and Pathology, University of Leeds, Cancer Research Building, St James's University Hospital, Leeds, LS9 7TF, UK.
Rosamonde E
RE
Banks
Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.|McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
Mark
M
Lathrop
Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.|McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
Guillaume
G
Bourque
Department of Human Genetics, McGill University, 1205 Dr Penfield Avenue, Montreal, QC, H3A 1B1, Canada.|McGill University and Genome Quebec Innovation Centre, 740 Doctor Penfield Avenue, Montreal, QC, H3A 0G1, Canada.
Yasser
Y
Riazalhosseini
D002292:Carcinoma, Renal Cell / Q000235:genetics*; D002470:Cell Survival / Q000235:genetics; D002872:Chromosome Deletion; D041322:Chromosomes, Human, Y; D056915:DNA Copy Number Variations; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D015778:Minor Histocompatibility Antigens / Q000235:genetics*
D015778:Minor Histocompatibility Antigens; D056466:Histone Demethylases; C095561:KDM5D protein, human