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<p>Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear. Here, we took advantage of a unique mouse model of intrinsic developmental heterogeneity (<i>Trim28</i><sup>+/D9</sup>) to investigate whether early-life epigenetic variation influences cancer susceptibility later in life. We found that heterozygosity of <i>Trim28</i> is sufficient to generate two distinct early-life epigenetic states associated with differing cancer susceptibility. These developmentally primed states exhibit differential methylation patterns at typically silenced heterochromatin, detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential, frequently mutated in human cancers and correlated with poor prognosis. This study provides genetic evidence that intrinsic developmental heterogeneity can prime individual, lifelong cancer susceptibility.</p>

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TRIM28-dependent developmental heterogeneity determines cancer susceptibility through distinct epigenetic states

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年1月24日

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  • Ilaria Panzeri,
  • Luca Fagnocchi,
  • Stefanos Apostle,
  • Megan Tompkins,
  • Emily Wolfrum,
  • Zachary Madaj,
  • Galen Hostetter,
  • Yanqing Liu,
  • Kristen Schaefer,
  • Chih-Hsiang Yang,
  • Alexis Bergsma,
  • Anne Drougard,
  • Erez Dror,
  • Zachary DeBruine,
  • Mao Ding,
  • Holly Dykstra,
  • Brooke Grimaldi,
  • Tim Gruber,
  • Qingchu Jin,
  • Christine W. Lary,
  • Mitchell J. McDonald,
  • Joseph H. Nadeau,
  • Andrea Parham,
  • Ildiko Polyak,
  • Jillian Richards,
  • Gabriel Seifert,
  • Ember Tokarski,
  • Raimond L. Winslow,
  • Darrell P. Chandler,
  • Daniel Schramek,
  • Timothy J. Triche Jr.,
  • John Andrew Pospisilik

摘要

Mutations in cancer risk genes increase susceptibility, but not all carriers develop cancer. Indeed, while DNA mutations are necessary drivers of cancer, only a small subset of mutated cells go on to cause the disease. To date, the mechanisms underlying individual cancer susceptibility remain unclear. Here, we took advantage of a unique mouse model of intrinsic developmental heterogeneity (Trim28+/D9) to investigate whether early-life epigenetic variation influences cancer susceptibility later in life. We found that heterozygosity of Trim28 is sufficient to generate two distinct early-life epigenetic states associated with differing cancer susceptibility. These developmentally primed states exhibit differential methylation patterns at typically silenced heterochromatin, detectable as early as 10 days of age. The differentially methylated loci are enriched for genes with known oncogenic potential, frequently mutated in human cancers and correlated with poor prognosis. This study provides genetic evidence that intrinsic developmental heterogeneity can prime individual, lifelong cancer susceptibility.