Abstract PR014: PVT1 fusion on extrachromosomal DNA (ecDNA) increases oncogene RNA stability and cancer cell growth

作者：Hyerim Yi, Shu Zhang, Matthew G. Jones, Julia A. Belk, Jason Swinderman, Quanming Shi, Ellis J. Curtis, Vishnu P Kanakaveti, Paul S. Mischel, Howard Y. Chang · 发表于：Molecular Cancer Therapeutics · 年份：2024 · DOI：10.1158/1538-8514.rnadrivers24-pr014 · 研究领域：Cancer Genomics and Diagnostics、RNA modifications and cancer

Abstract Extrachromosomal DNA (ecDNA), highly amplified circular DNA, is widespread in human cancers and serves as a primary location for oncogene amplification. Due to its dynamic structural rearrangement and asymmetric inheritance during cell division, ecDNA increases tumor genome complexity, contributing to drug resistance and shortened patient survival. Here, we show that ecDNA-mediated genomic amplification is highly associated with transcript fusion events, which are prevalent in cancer and often lead to tumor development. We discovered that transcripts with the highest fusion events originate from genes amplified on ecDNA across ecDNA(+) cell lines. Notably, PVT1 (Plasmacytoma Variant Translocation 1) long noncoding RNA, which is known to be a hotspot for chromosomal translocation, is the most frequently fused RNA species in MYC/PVT1-amplified ecDNA(+) cancer cells. Exon 1 of PVT1 is the predominant fusion partner and confers RNA stability, increasing the RNA abundance of the partner oncogene. Using a model cell line with PVT1-MYC fusion on ecDNA, we found that RNA expression of PVT1-MYC increases in vivo in an ecDNA-dependent manner, while canonical MYC does not show a prominent increase. Additionally, ectopic expression of PVT1- MYC in MYC-depleted cancer cells provides higher rescue efficiency than canonical MYC. In contrast, a PVT1-MYC mutant that is unable to enhance RNA stability fails to rescue, highlighting the functional significance of PVT1-mediated RNA stabi...