Abstract 6857: Sex differences in the gene regulatory mechanisms of lung aging and their implications in lung cancer risk.

Abstract Lung cancer is the leading cause of cancer-related deaths worldwide. While disease risk increases with age in both sexes, there is significant difference in prevalence between males and females, even after adjusting for smoking history. We use novel computational models to infer individual-specific gene regulatory networks integrating transcriptomic and epigenomic data. These networks represent gene regulatory interactions between transcription factors, DNA methylation levels and target gene expression at individual-level resolution. We use sex-specific transcription factor motif and protein-protein interaction data as prior information in our network estimation to further highlight sex-specific regulatory interactions. Comparing gene regulatory networks from healthy normal lung tissue from the Genotype Tissue Expression Project across varying ages, we observe that genes involved in immune response , cell proliferation, and cancer-related pathways are differentially regulated with age in a sex-differential manner. Aging-related gene regulatory changes are influenced by estrogen receptor and androgen receptor transcription factors in females, with significant inflection points between ages 40 and 60. Examining individual-specific networks from lung adenocarcinoma samples from The Cancer Genome Atlas, we observe that aging-related gene regulatory changes converge with cancer-associated regulatory patterns. Critically, at any given age, regulatory patterns of immune and cell proliferation pathways in females without a history of smoking resemble disease-related patterns significantly more than their male counterparts. This finding highlights the role of aging-related gene regulatory changes in elevating cancer risk with age, and disproportionately so in females. Individuals with a history of smoking have regulatory signatures more akin to accelerated aging, resembling patterns observed in older never-smokers, and show greater similarity with disease states. These findings underscore age- and sex-specific mechanisms of lung cancer susceptibility, independent of smoking exposure, and highlight the need for tailored prevention strategies, informed by individual age and sex. Citation Format: Enakshi Saha, . Sex differences in the gene regulatory mechanisms of lung aging and their implications in lung cancer risk 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 6857.