Identification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network

Sue Haupt (), Franco Caramia, Alan Herschtal, Thierry Soussi, Guillermina Lozano, Hu Chen, Han Liang, Terence P. Speed and Ygal Haupt
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Sue Haupt: Tumor Suppression Laboratory, Peter MacCallum Cancer Centre
Franco Caramia: Tumor Suppression Laboratory, Peter MacCallum Cancer Centre
Alan Herschtal: Department of Biometrics Novotech
Thierry Soussi: Karolinska Institute, Cancer Center Karolinska
Guillermina Lozano: The University of Texas, MD Anderson Cancer Center
Hu Chen: Baylor College of Medicine
Han Liang: Baylor College of Medicine
Terence P. Speed: Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research
Ygal Haupt: Tumor Suppression Laboratory, Peter MacCallum Cancer Centre

Nature Communications, 2019, vol. 10, issue 1, 1-12

Abstract: Abstract The disproportionately high prevalence of male cancer is poorly understood. We tested for sex-disparity in the functional integrity of the major tumor suppressor p53 in sporadic cancers. Our bioinformatics analyses expose three novel levels of p53 impact on sex-disparity in 12 non-reproductive cancer types. First, TP53 mutation is more frequent in these cancers among US males than females, with poorest survival correlating with its mutation. Second, numerous X-linked genes are associated with p53, including vital genomic regulators. Males are at unique risk from alterations of their single copies of these genes. High expression of X-linked negative regulators of p53 in wild-type TP53 cancers corresponds with reduced survival. Third, females exhibit an exceptional incidence of non-expressed mutations among p53-associated X-linked genes. Our data indicate that poor survival in males is contributed by high frequencies of TP53 mutations and an inability to shield against deregulated X-linked genes that engage in p53 networks.

Date: 2019
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DOI: 10.1038/s41467-019-13266-3

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