Sex Differences in DNA Methylation and Gene Expression Reveal Distinct Molecular Programs in Muscle-Invasive Bladder Cancer
Abstract
Sex differences in muscle-invasive bladder cancer (MIBC) incidence and outcomes are well established, but the underlying epigenetic mechanisms remain poorly understood. We integrated genome-wide DNA methylation and RNA sequencing to define sex-associated epigenetic and transcriptional programs in human MIBC and evaluated their conservation in the N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse model. Male tumors exhibited substantially broader DNA methylation remodeling, whereas female tumors showed prominent epithelial-mesenchymal transition (EMT) and mitotic programs. These sex-associated patterns were recapitulated in BBN tumors, with substantial conservation of human MIBC methylation changes and transcriptional programs. Cross-species integration identified conserved methylation-regulated genes, including ADAMTS12, ONECUT2, and PPP2R2C, whose expression increased following pharmacologic DNA demethylation and was associated with disease progression. Given the potential role of sex chromosomes in sex-associated molecular differences in MIBC, we evaluated X-chromosome inactivation escape and Y-linked gene expression. Reduced expression of an X-chromosome inactivation escape signature was independently associated with shorter overall survival, while reduced Y-linked gene expression was associated with immune activation. Together, these findings identify conserved sex-associated epigenetic programs in MIBC and demonstrate distinct methylation, transcriptional, and sex-chromosome features that may contribute to sex differences in bladder cancer biology and clinical outcomes.
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BibTeX
@misc{doshi2026differences,
title = {{Sex Differences in DNA Methylation and Gene Expression Reveal Distinct Molecular Programs in Muscle-Invasive Bladder Cancer}},
author = {Bhavisha Doshi and Eduardo Cortes Gomez and Barbara A. Foster and Jianmin Wang and Norbert Sule and Wendy J. Huss and Anna Woloszynska},
howpublished = {bioRxiv},
year = {2026},
month = oct,
doi = {10.64898/2026.10.21.760777},
url = {https://www.biorxiv.org/content/10.64898/2026.10.21.760777v1},
note = {CC BY-NC},
}
RIS
TY - UNPB
TI - Sex Differences in DNA Methylation and Gene Expression Reveal Distinct Molecular Programs in Muscle-Invasive Bladder Cancer
AU - Bhavisha Doshi
AU - Eduardo Cortes Gomez
AU - Barbara A. Foster
AU - Jianmin Wang
AU - Norbert Sule
AU - Wendy J. Huss
AU - Anna Woloszynska
PY - 2026
DA - 2026/10/21
PB - bioRxiv
DO - 10.64898/2026.10.21.760777
UR - https://www.biorxiv.org/content/10.64898/2026.10.21.760777v1
AB - Sex differences in muscle-invasive bladder cancer (MIBC) incidence and outcomes are well established, but the underlying epigenetic mechanisms remain poorly understood. We integrated genome-wide DNA methylation and RNA sequencing to define sex-associated epigenetic and transcriptional programs in human MIBC and evaluated their conservation in the N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) mouse model. Male tumors exhibited substantially broader DNA methylation remodeling, whereas female tumors showed prominent epithelial-mesenchymal transition (EMT) and mitotic programs. These sex-associated patterns were recapitulated in BBN tumors, with substantial conservation of human MIBC methylation changes and transcriptional programs. Cross-species integration identified conserved methylation-regulated genes, including ADAMTS12, ONECUT2, and PPP2R2C, whose expression increased following pharmacologic DNA demethylation and was associated with disease progression. Given the potential role of sex chromosomes in sex-associated molecular differences in MIBC, we evaluated X-chromosome inactivation escape and Y-linked gene expression. Reduced expression of an X-chromosome inactivation escape signature was independently associated with shorter overall survival, while reduced Y-linked gene expression was associated with immune activation. Together, these findings identify conserved sex-associated epigenetic programs in MIBC and demonstrate distinct methylation, transcriptional, and sex-chromosome features that may contribute to sex differences in bladder cancer biology and clinical outcomes.
SN - 2692-8205
ER -