Panzeri Ilaria, Fagnocchi Luca, Apostle Stefanos, Tompkins Megan, Wolfrum Emily, Madaj Zachary, Hostetter Galen, Liu Yanqing, Schaefer Kristen, Yang Chih-Hsiang, Bergsma Alexis, Drougard Anne, Dror Erez, Chandler Darrell P, Schramek Daniel, Triche Timothy J, Pospisilik John Andrew
Department of Epigenetics, Van Andel Institute, Grand Rapids, MI, USA.
Department of Epigenetics, Max Planck Institute of Immunobiology and Epigenetics, Freiburg, Germany.
Nat Cancer. 2025 Feb;6(2):385-403. doi: 10.1038/s43018-024-00900-3. Epub 2025 Jan 24.
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) 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.
癌症风险基因的突变会增加易感性，但并非所有携带者都会患癌。事实上，虽然DNA突变是癌症的必要驱动因素，但只有一小部分突变细胞会引发疾病。迄今为止，个体癌症易感性的潜在机制仍不清楚。在这里，我们利用一种独特的内在发育异质性小鼠模型（Trim28）来研究生命早期的表观遗传变异是否会影响生命后期的癌症易感性。我们发现，Trim28的杂合性足以产生两种不同的生命早期表观遗传状态，这两种状态与不同的癌症易感性相关。这些发育预编程状态在通常沉默的异染色质上表现出不同的甲基化模式，最早在10日龄时就可检测到。差异甲基化位点富含具有已知致癌潜力的基因，这些基因在人类癌症中经常发生突变，并与不良预后相关。这项研究提供了遗传学证据，证明内在发育异质性可以预编程个体终身的癌症易感性。
