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.
Highlights
The disproportionately high prevalence of male cancer is poorly understood
TCGA offers the rates of cancer-associated TP53 mutations from random cancer sampling across the sexes, but does not claim to be representative of population incidence
The pathogenic definition is built on the observation that most cancer-associated TP53 mutations occur in its DNAbinding domain and cause interruption of p53 function[10]
Summary
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. In a compound mutant p53 mouse model that we generated, males developed more aggressive cancers and reduced lifespan than females[8] This triggered us to investigate the connection between p53 and cancer sex disparity in non-reproductive cancers. The activities attributed to p53, include the four key processes recently identified through gene expression analyses to link to cancer sex disparity: (1) immune response, (2) apoptosis and cell cycle, (3) metabolism-related and (4) DNA-repair and p53-pathways (using standard autosome pathways of the gene set enrichment analysis (GSEA)[2]. In healthy individuals, inherited genetic variants in the standard p53-pathways were more frequent than for all other pathways and linked to cancer exclusively, and not other diseases[16] These findings highlight the importance of p53 and its autosome partner proteins as the greatest natural deterrent against cancer. In this study of non-reproductive cancers, we identified three novel layers of risk for cancer sex disparity that are critically affected by p53 status and subject to the function and expression of its X-chromosome interactors
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