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

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; PERMUTE; Darrell P Chandler; Daniel Schramek; Timothy J Triche Jr; John Andrew Pospisilik

doi:10.1038/s43018-024-00900-3

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

Nat Cancer. 2025 Jan 24. doi: 10.1038/s43018-024-00900-3. Online ahead of print.

Authors

Ilaria Panzeri^{1

2}, Luca Fagnocchi³, Stefanos Apostle³, Megan Tompkins⁴, Emily Wolfrum⁵, Zachary Madaj⁵, Galen Hostetter⁶, Yanqing Liu³, Kristen Schaefer^{3

7}, Chih-Hsiang Yang^{3

8

9}, Alexis Bergsma^{3

10}, Anne Drougard³, Erez Dror⁸; PERMUTE; Darrell P Chandler³, Daniel Schramek^{11

12}, Timothy J Triche Jr^{3

13

14}, John Andrew Pospisilik^{15

16}

Collaborators

PERMUTE:
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

Affiliations

¹ Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA. [email protected].
² Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. [email protected].
³ Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
⁴ Vivarium and Transgenics Core, Van Andel Institute, Grand Rapids, MI, USA.
⁵ Bioinformatics and Biostatistics Core, Van Andel Institute, Grand Rapids, MI, USA.
⁶ Pathology and Biorepository Core, Van Andel Institute, Grand Rapids, MI, USA.
⁷ Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH, USA.
⁸ Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
⁹ Department of Biochemistry and Molecular Biotechnology, University of Massachusetts Chan Medical School, Worcester, MA, USA.
¹⁰ Parkinson's Disease Center, Department of Neurodegenerative Science, Van Andel Institute, Grand Rapids, MI, USA.
¹¹ Centre for Molecular and Systems Biology, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada.
¹² Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
¹³ Department of Pediatrics, MSU College of Human Medicine, East Lansing, MI, USA.
¹⁴ Department of Translational Genomics, University of Southern California, Los Angeles, CA, USA.
¹⁵ Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA. [email protected].
¹⁶ Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany. [email protected].

PMID: 39856421
DOI: 10.1038/s43018-024-00900-3

Abstract

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.