Sexual dimorphism in cancer incidence and outcome is widespread. Understanding the underlying mechanisms is fundamental to improve cancer prevention and clinical management. Sex disparities are particularly striking in kidney cancer: across diverse populations, men consistently show unexplained 2-fold increased incidence and worse prognosis. We have characterized genome-wide expression and regulatory networks of 609 renal tumors and 256 non-tumor renal tissues. Normal kidney displayed sex-specific transcriptional signatures, including higher expression of X-linked tumor suppressor genes in women. Sex-dependent genotype-phenotype associations unraveled women-specific immune regulation. Sex differences were markedly expanded in tumors, with male-biased expression of key genes implicated in metabolism, non-malignant diseases with male predominance and carcinogenesis, including markers of tumor infiltrating leukocytes. Analysis of sex-dependent RCC progression and survival uncovered prognostic markers involved in immune response and oxygen homeostasis. In summary, human kidney tissues display remarkable sexual dimorphism at the molecular level. Sex-specific transcriptional signatures further shape renal cancer, with relevance for clinical management.

Clinic of Urology Clinical Center of Serbia University of Belgrade Faculty of Medicine 11000 Belgrade Serbia

Department of Cancer Epidemiology and Genetics Masaryk Memorial Cancer Institute 60200 Brno Czech Republic

Department of Environmental Epidemiology Nofer Institute of Occupational Medicine 91 348 Lodz Poland

Department of Environmental Health National Institute of Public Health 050463 Bucharest Romania

Department of Epidemiology and Prevention Russian N N Blokhin Cancer Research Centre 115478 Moscow Russian Federation

Department of Public Health and Preventive Medicine Charles University 2nd Faculty of Medicine 15006 Prague Czech Republic

Faculty of Medicine School of Public Health Imperial College London W21NY London UK

International Organisation for Cancer Prevention and Research 11070 Belgrade Serbia

Laboratory of Population Health Max Planck Institute for Demographic Research 18057 Rostock Germany

Science and Research Center Faculty of Health Sciences Palacky University 77900 Olomouc Czech Republic

Section of Genetics International Agency for Research on Cancer 69372 Lyon France

Unit of Cancer Epidemiology Department of Medical Sciences University of Turin 8 10124 Turin Italy

Université Paris Saclay CEA Centre National de Recherche en Génomique Humaine 91057 Evry France

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Understanding the biological processes of kidney carcinogenesis: an integrative multi-omics approach