Abstract 209: Differentially expressed genes associated with disease-specific chromatin changes in oral cancer have a significant correlation with overall survival

Abstract Globally, there are ∼400, 000 Oral Squamous Cell Carcinoma (OSCC) cases diagnosed each year and ∼200, 000 deaths. The 5-year survival rate for OSCC is only ∼50%, and this has not improved in decades. In other cancers, recent studies have shown that chromatin structure changes, impacting gene regulatory regions known as enhancers, can play a key role in gene expression dysregulation. Enhancers, with their transcription factor binding sites, attract transcription factors that, along with coactivators, assemble the transcription machinery. Super-enhancers, dense clusters of enhancers, amplify this assembly. The addition of coactivators like histone acetyltransferases and methyltransferases remodels chromatin, affecting DNA accessibility. Research has not been done using primary OSCC tissues. I propose that in OSCC, specific aberrations in chromatin organization lead to alterations in gene expression associated with cancer. Furthermore, I hypothesize that these chromatin anomalies are not random but concentrated at certain genomic loci, which act as 'hotspots' for regulatory disruption. Chromatin immunoprecipitation sequencing (ChIP-seq) for the active enhancer marker H3K27ac was performed using 20 pairs of OSCC-tongue patient matched tumor and normal tissues. From the H3K27ac ChIP-seq data, disease-specific enhancers and super-enhancers, which are present either only in tumor or normal chromatin, were identified. There were 22, 336 “hot spots” found where the disease-specific change is in more than one patient. To identify differentially expressed genes (DEGs) regulated by those (super)enhancers, RNA extracted from these tissues was submitted for sequencing (RNA-seq) and analyzed. DEGs that are within the regulatory range of disease-specific enhancers and super-enhancers were identified and evaluated for their impact on OSCC. Tumor-specific enhancers cause upregulation of the target gene, whereas normal-specific enhancers that are absent in the tumor are associated with a gene downregulated in the tumor. Many DEGs in the regulatory range of disease-specific enhancers and super-enhancers were found to have a significant association with overall survival. Such elucidation of the role of chromatin structural alterations in OSCC paves the way for a deeper comprehension of gene expression dysregulation and heralds a new frontier in the development of innovative therapeutic strategies. Citation Format: Diane Terry, Andrey Loginov, Jennifer Coleman, Amy Plotkin, Ashley Johnson, Carol Robles, Joshua Lubek, Donita Dyalram, Kyle Hatten, Daria Gaykalova. Differentially expressed genes associated with disease-specific chromatin changes in oral cancer have a significant correlation with overall survival [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 209.