Abstract 1122: Pan-cancer analysis reveals roles of retrotransposon-fusion RNAs

Abstract Transposons comprise half of the human genome and some create novel insertions in human germ cells and somatic tissues of healthy and diseased individuals. These genetic elements may be an abundant yet underexplored source of immunogenic molecules that create chimeric transcripts composed of transposons and non-transposons. However, it remains challenging to accurately identify such transposon-fusion events from short RNA-seq reads mainly due to the repetitive nature of transposon sequences and error-prone read alignment near exon-intron junctions, and there are few existing methods for such detection. We developed a computational pipeline, rTea (RNA Transposable Element Analyzer) to detect transposons-fusion transcripts from RNA-seq data. Using rTea, we performed a pan-cancer analysis of 10,257 cancer samples across 34 cancer types as well as 2,994 normal tissue samples from the TCGA/ICGC, our unpublished colorectal cancer cohort, and the GTEx consortia. Among normal human tissues, higher fusion loads were found most notably in the testis and to a lesser extent in other tissues that have been characterized as immune-privileged. Somatic fusions found in cancer were enriched in known cancer genes, implicating their contribution to tumorigenesis. We also found distinct epigenetic and tumorigenic mechanisms underlying fusions from different transposon families. Through in silico immunogenicity modeling and experimental validation, we confirmed the MHC-I binding and CD8+ T cell activation by peptides derived from transposon fusions to the extent comparable to EBV viruses. Our findings highlight endogenous retroelements as novel therapeutic targets and a significant source of neoantigens. Citation Format: E. Alice Lee, Boram Lee, Yoonjoo Choi, Junseok Park, Adam Voshall, Eduardo Maury, Yeeok Kang, Yeon Jeong Kim, Jin-Young Lee, Hye-Ran Shim, Si-Cho Kim, Hoang Bao Khanh Chu, Da-Won Kim, Minjeong Kim, Eun-Ji Choi, Kyungsoo Ha, Jung Kyoon Choi, Yongjoon Kim, Woong-Yang Park. Pan-cancer analysis reveals roles of retrotransposon-fusion RNAs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1122.