Abstract A004: Repetitive elements and viral mimicry co-evolve in pancreatic cancer

Abstract

Abstract Overexpression of repetitive DNA is an emerging hallmark of human cancers and several repeats, such as SINE elements and satellite, transcribe immunostimulatory RNA that mimic features associated with viral infection. However, the extent to which specific repeat families affect tumor evolution and the immune microenvironment in a pro-or anti-tumorigenic manner remains poorly understood. We present an integrated, evolutionary multi-omic analysis pf repeat evolution in multiregion-sampled human metastatic and primary pancreatic cancers for the first time. We found that LINE-1 (L1) somatic insertion location coincides with tumor evolution. Moreover, we found L1 activity is negatively correlated with immunogenic SINE element expression. Two orthogonal metrics were used in quantifying immunogenicity of SINE elements: IFN signature and capability of forming dsRNA, where both methods revealed that evolutionary young SINE elements have stronger correlation with IFN signatures and are more likely to form dsRNAs. Moreover, the anti-correlation between L1 activity and SINE expression is validated through both immunohistological analysis of human samples and pancreatic cancer cell lines. In the end, we proposed that the model of hypoactive L1 is beneficial for tumors by suppression of immunogenic SINE elements through either their direct reverse transcription or accelerating their degradation. Our analysis therefore sheds light on the evolutionary role of dark matter repeats in a tumor’s adaptation to immunogenic vulnerabilities. Citation Format: Siyu Sun. Repetitive elements and viral mimicry co-evolve in pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr A004.