Abstract The purpose of this study includes characterizing the transcriptomic impact of cigarette smoke (CS) across many human tissue types, while incorporating data from groups underrepresented in genetics research. CS, a leading cause of death worldwide, contains carcinogens that adversely affect the health of many tissues. Although incompletely characterized, the transcriptomic profiles of non-cancerous tissues from smokers may elucidate molecular pathways triggering or defending against tumorigenesis. However, there is a need for smoking-related transcriptomic studies containing data from diverse racial/ethnic groups to investigate how CS contributes to cancer health disparities. While the racial distribution of our donors does not fully reflect that of the U.S. population, our findings may be foundational for future studies examining how CS-induced molecular alterations contribute to cancer disparities. Using a multi-omics approach, we analyzed RNA-seq and small RNA-seq data from samples collected by the Genotype-Tissue Expression (GTEx) project to assess mechanisms promoting or mitigating carcinogenesis in non-diseased tissue types. We examined associations between CS and 1) mRNA expression, 2) microRNA (miRNA) expression, 3) splicing, and 4) RNA-editing in 40 tissue and two cell types. Sample sizes ranged from n=130 to n=793 across 904 donors (∼69% have a smoking history). Regression models adjusting donor-level characteristics and surrogate variables were used to identify CS-associated features. CS was associated (FDR 0.05) with mRNA and miRNA expression in 28 and five tissue types, respectively. Lung showed the highest number of CS-associated mRNAs (3,368), followed by thyroid (935), and the heart’s left ventricle (442). Lung (8) and tibial nerve (3) had the highest number of CS-associated miRNAs. Over 100 mRNAs were associated with smoking in at least four tissues including AHRR (26 tissue types), GPR15 (25), CYP1A1 (22), CYP1B1 (14). Dozens of genes within the immunoglobulin (Ig) Kappa (chr2), Heavy chain (chr14), and Lambda (chr22) loci were responsive to CS in stomach, skin, whole blood. Analyses of CS and tissue-specific immune repertoires are ongoing. Overrepresentation analyses indicate that immune response gene sets are enriched among CS-associated genes in these tissues. Hallmark gene set enrichment analyses of tissue types with 250 CS-associated genes showed enrichment of oxidative phosphorylation, MYC targets, TNF-α signaling suggesting a CS-induced immune and cancer response. CS-associated splicing events were present in 16 tissue types, including lung (21 events), thyroid (13), and colon (4). Associations between CS and RNA-editing events were not observed. Future directions include integrative approaches to determine if miRNAs are mediators responsible for smoking-associated changes in gene expression and splicing. In conclusion, using a racially diverse cohort, our results characterize tissue-specific, transcriptomic impacts of CS, including those susceptible to smoking-driven cancers associated with health disparities. Citation Format: Letonia Copeland-Hardin, Lin Tong, Kathryn Demanelis, Brandon Pierce. The transcriptomic impact of cigarette smoke across human tissue types abstract. In: Proceedings of the 18th AACR Conference on the Science of Cancer Health Disparities; 2025 Sep 18-21; Baltimore, MD. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2025;34(9 Suppl):Abstract nr B156.
Copeland-Hardin et al. (Thu,) studied this question.