Identification of cancer sex-disparity in the functional integrity of p53 and its X chromosome network
Open accessAbstract
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.
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- Authors
- Haupt, S., Caramia, F., Herschtal, A., Soussi, T., Lozano, G., Chen, H., Liang, H., Speed, T. P., & Haupt, Y.
- Affiliations
- The University of Melbourne (AU)
- Inserm (FR)
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Haupt, Sue
- ORCID
- Venue
- Nature Communications
- Published
- 2019-11-26
- Volume
- 10
- Issue
- 1
- Pages
- 5385-5385
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6879765
- OpenAlex
- W2991018046
- Cited by
- 94
- References
- 85
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 18 · 2023: 15 · 2022: 21 · 2021: 13 · 2020: 5 · 2017: 1
- FWCI
- 4.07
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- HAL (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Breast Cancer Foundation (IN-16-042)
- Peter MacCallum Foundation (1123057)
- University of Texas MD Anderson Cancer Center
- National Health and Medical Research Council (1054618, 1123057)
- National Cancer Institute (P30CA016672)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- sex differences in cancer, TP53 mutation, p53, X chromosome, X-linked genes, tumor suppressor, cancer survival, sex-biased gene expression
- MeSH terms
- Female, Humans, Male, Neoplasms, Sex Factors, United States, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, SEER Program, Chromosomes, Human, X, Genes, X-Linked, Exome, Mutation Rate, Protein Interaction Maps
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