Abstract 1446: Gene expression characteristics of the young tongue cancer patient

Abstract Introduction: Historical risk factors for tongue cancer include age, chronic exposure to tobacco and alcohol use. Smoking-related tongue cancer has declined due to active anti-tobacco campaigns in developed countries, yet the incidence of tongue cancer has increased, particularly in women and patients under in a younger age group. This study aims to investigate differences in the genomic processes driving oncogenesis in young and old patients with tongue cancer. Methods: We perform laser-capture microdissection on 54 formalin-fixed paraffin-embedded (FFPE) tongue cancer samples collected from glossectomy surgeries performed from 2009 - 2020 at the National University Hospital, Singapore. To ensure purity, tumor epithelial and microenvironment compartments were separately microdissected for each specimen. Gene expression libraries for each compartment were prepared using a specialized RNA-Seq technique optimized for tiny amounts of FFPE material, followed by next generation sequencing. Differential gene expression and geneset enrichment analysis was performed, comparing patients aged ≤ 50 years (Young Group) and > 50 years (Old Group). Results: We present a large cohort of 149 microdissected gene expression libraries, including 65 tumor epithelial, 61 microenvironment and 23 normal-adjacent regions. Principal component analysis showed distinct clusters of tumor epithelial and microenvironment gene expression profiles, confirming sample purity. Kaplan-Meier survival analysis revealed poorer outcomes in the Young Group compared to the Old Group. Analysis of the tumor epithelial compartment revealed that young and old tongue cancers exhibited similar gene expression profiles. Notably, there were few differentially expressed genes in the Young Group compared to the Old Group. However, in the microenvironment compartment, we observed that genes involved in immune response were downregulated in the Young Group, including cell killing (Normalised Effect Size =-1.80, p-adj=0.00704) and leukocyte-mediated cytotoxicity (NES=-1.77, p-adj=0.0367). Instead, genes involved in muscle cell development (NES=1.93, p-adj=0.000301) were enriched in the Young Group, indicating the presence of tongue muscle tissue instead of an inflamed tumor microenvironment. Conclusion: The “young tongue cancer” patient has been suggested to be a unique and aggressive biological entity that exhibits distinct epidemiological and clinical characteristics. Our findings indicate that while tumor epithelial compartment in young and old tongue cancers have similar gene expression profiles, differences in the tumor microenvironment, particularly an immune-cold phenotype in young tumors, may explain their poorer survival outcomes and aggressive behavior. Establishing these biological differences will provide critical insights and support the development of treatment strategies to improve survival outcomes for these patients. Citation Format: Bryan Yichong Shi, Yi Ren, Wei Keat Teo, Jerome Wen Jun Bin, Joseph W Foley, Chor Hiang Siow, Kwok Seng Loh, Bingcheng Wu, Joshua K Tay, Donovan Eu. Gene expression characteristics of the young tongue cancer patient [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 1446.