Abstract 1935: Sperm-borne epigenetic changes modulate offspring tumor susceptibility.

Abstract Epigenetic mechanisms play important roles in cancer development and progression. We previously found that heritable epigenetic perturbations induced by paternal depletion of the epigenetic regulator KDM6A may increase susceptibility to lung adenoma in a mouse model. Understanding the mechanism of this effect will expand our understanding of cancer heritability and the role of epigenetic modifications in tumorigenesis. Here, we investigate the mechanism by which paternal KDM6A loss mediates cancer susceptibility in the lung using transcriptomic analysis in healthy lung tissue and lung tumors of offspring. We evaluated changes in gene expression in healthy lung tissue of offspring of Kdm6a-mutant fathers that could promote tumorigenesis in the genetically wild-type offspring using single cell RNA sequencing (scRNA-seq). Notably, we observed a drastic reduction in neutrophils and an enrichment of lymphocytes, as well as altered transcriptomes in these immune populations, in pre-cancer lung tissue of adult male offspring. Our preliminary results imply that a perturbed epigenetic landscape starting from birth may induce chronic inflammatory changes that contributes to cancer, and suggest that risk of cancer could be predicted in early life. Strikingly, KRAS-driven lung tumors from offspring of KDM6A-depleted fathers show reduced expression of genes regulating normal cilium organization and function. In addition, among genes with loss of the activating histone modification H3K4me3 at their promoters in KDM6A depleted-sperm, we found a total of 85 that were differentially expressed in pre-cancer lung tissue, and that this set of genes was enriched for the RAS/MAPK signaling pathway. Genes that regulate Ras and Rho GTPase, including Sos2, Grb2, and Rhoq, were moderately upregulated in leukocytes, suggesting that histone modification has the potential to transmit a perturbed epigenome and lead to dysregulated transcriptome across generations. Together, our data indicate that heritable epigenetic disruption of cilia development and leukocyte function may confer a predisposition to cancer in lung tissue. Citation Format: Zihan (Hannah) Yin. Sperm-borne epigenetic changes modulate offspring tumor susceptibility [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 1935.