Cáceres, AlejandroPérez Jurado, Luis AlbertoAlegret-García, AlbertDwaraka, Varun B.Smith, Ryan WalterGonzález, Juan Ramón2025-05-062025-05-062025Cáceres A, Pérez-Jurado LA, Alegret-García A, Dwaraka VB, Smith R, González JR. Defective X-chromosome inactivation and cancer risk in women. Commun Biol. 2025 Feb 22;8(1):289. DOI: 10.1038/s42003-025-07691-y2399-3642http://hdl.handle.net/10230/70303X-chromosome inactivation (XCI) is a fundamental mechanism in placental mammals that compensates for gene dosage differences between sexes. Using methylation levels of genes under XCI, we establish defective levels of XCI as a new source of interindividual variation among cancer types in females, characterized by a significant and consistent lowering of XIST expression and enrichment of differentially expressed genes under XCI. We show that defective XCI is an additive factor to the cancer risk of XCI escape deregulation in women. Defective XCI of more than 10% has an attributable risk of 40% among 12 different cancers from The Cancer Genome Atlas. Validations between independent studies of breast cancer samples show that defective XCI increases triple-negative subtype frequency, decreases survival rates, and is reduced by chemotherapy treatment. Mechanistically, it is associated with somatic mutations at TP53 and top MYC gains. In independent studies, defective XCI is detectable in blood and increases with aging, menopause, and cancer diagnosis.application/pdfeng© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.info:eu-repo/semantics/articlehttp://dx.doi.org/10.1038/s42003-025-07691-yCancer epigeneticsDiagnostic markersinfo:eu-repo/semantics/openAccess