Abstract B005: The functional role of transposable element-oncogene chimeric transcript during cancer progression

Abstract Nearly half of the human genome is composed of transposable elements (TEs), which were once considered “junk” DNA due in part to their repetitive and non-coding characteristics. However, TEs are now emerging as important regulators of gene activity, especially when they escape typical epigenetic silencing mechanisms like DNA methylation and histone modifications. When activated, TEs can contribute sequences that are exploited as disruptors of genomic stability or novel gene regulatory elements, making them important factors in both development and disease, including cancer. In cancer, these previously silenced elements can act as alternative promoters of oncogenes, leading to the production of TE-chimeric transcripts in a process called “onco-exaptation”. While these oncoexaptation events are reported to be widespread across many cancers, only a few TE-chimeric transcripts have been validated as active contributors to cancer progression. Additionally, it remains unclear whether these TE-chimeric transcripts are merely a consequence of the inherent genomic instability in cancer or whether they can initiate cancer. To address these gaps, we designed a cDNA overexpression library incorporating our previously identified pan-cancer TE-chimeric transcript candidates. This library is used in early passage (EP) BJ fibroblast, a cell line known for its transformation potential in the well-established Weinberg transformation model, which allows us to systematically investigate these onco-exaptation events during cancer progression. Our initial analyses indicate that most TE-chimeric oncogenes are not expressed in EP fibroblast, but are activated in subsequent transformation stages following hTERT, SV40 and HRas induction, underscoring the model viability. We are currently using this model to distinguish TE-chimeric transcripts that act as drivers (TE-chimeric oncogenes) from those requiring previous vulnerabilities, such as telomere inactivation by hTERT or p53 and Rb inactivation by SV40. Ultimately, this work will identify novel biomarkers and therapeutic targets, enhance insights into gene regulation, and provide opportunities for early detection and intervention. These findings have the potential to improve cancer treatment and patient outcomes. Citation Format: Wesley N Saintilnord, Yixin Wu, Yonghao Liang, Ting Wang. The functional role of transposable element-oncogene chimeric transcript during cancer progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Methylation, Clonal Hematopoiesis, and Cancer; 2025 Feb 1-4; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2025;85(3 Suppl):Abstract nr B005.