{
  "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.",
  "abstract_shown": true,
  "affiliations": [],
  "article_type": "New results",
  "arxiv": null,
  "author_total": 7,
  "authors": [
    {
      "name": "Bhavisha Doshi",
      "orcid": "0000-0003-3411-4770"
    },
    {
      "name": "Eduardo Cortes Gomez",
      "orcid": "0000-0002-0966-6488"
    },
    {
      "name": "Barbara A. Foster",
      "orcid": "0000-0003-0459-7011"
    },
    {
      "name": "Jianmin Wang",
      "orcid": "0000-0001-7527-0409"
    },
    {
      "name": "Norbert Sule",
      "orcid": "0009-0003-9244-0096"
    },
    {
      "name": "Wendy J. Huss",
      "orcid": "0000-0002-0812-8696"
    },
    {
      "name": "Anna Woloszynska",
      "orcid": "0000-0001-5279-9414"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fskvgwtfvwkxg.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.21.760777",
  "fulltext_url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760777v1.full",
  "id": "fskvgwtfvwkxg",
  "issns": [
    "2692-8205"
  ],
  "landing_url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760777v1",
  "language": "en",
  "licence": "CC-BY-NC",
  "licence_label": "CC BY-NC",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nc/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "biorxiv",
      "cancer biology"
    ],
    [
      "heading",
      "Article"
    ],
    [
      "openalex",
      "1312|Epigenetics and DNA Methylation"
    ]
  ],
  "openalex": "W7223401116",
  "pdf_url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760777v1.full.pdf",
  "pmcid": "PMC13738737",
  "pmid": "42996125",
  "published": "2026-10-21",
  "publisher": "Cold Spring Harbor Laboratory Preprints",
  "ris": "https://research.draconitic.com/paper/fskvgwtfvwkxg.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:29:18Z",
      "native_id": "10.64898/2026.10.21.760777",
      "source": "biorxiv",
      "url": "https://www.biorxiv.org/content/10.64898/2026.10.21.760777v1"
    },
    {
      "first_seen": "2026-11-09T12:23:40Z",
      "native_id": "PMC13738737",
      "source": "pmc",
      "url": "https://doi.org/10.64898/2026.10.21.760777"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "biorxiv:cancer biology",
      "subfield": "oncology"
    }
  ],
  "title": "Sex Differences in DNA Methylation and Gene Expression Reveal Distinct Molecular Programs in Muscle-Invasive Bladder Cancer",
  "title_text": "Sex Differences in DNA Methylation and Gene Expression Reveal Distinct Molecular Programs in Muscle-Invasive Bladder Cancer",
  "type": "preprint",
  "updated_at": "2026-11-09T12:23:40Z",
  "url": "https://research.draconitic.com/paper/fskvgwtfvwkxg",
  "venue": "bioRxiv",
  "versions": []
}