Abstract LB-303: Transposable element insertions impact the mutational landscape of breast cancer genomes and disease onset

Abstract

Abstract More than 50% of the human genome consists of transposable elements (TE), which mostly remain inactive and relatively stable in healthy individuals. These elements, commonly known as “jumping genes,” are sequences of DNA that are mobile and can change positions in the genome. However, only certain classes of retrotransposons (ALU, SVA, ERV and L1) are believed to be active in the human genome. Most TEs transpose by a “copy-and-paste” mechanism via transcription from DNA to an RNA intermediate followed by reverse transcription back to DNA and subsequent insertion of the copied DNA into the genome. In healthy individuals, this mechanism is silenced by various epigenetic pathways such as the piRNA pathway which helps silence the transcribed TE RNA intermediates. However during cancer, some retrotransposons are believed to become active due to loss of this epigenetic silencing and DNA damage repair mechanisms. In this study, we analyzed somatic and germline TE insertions in 77 TCGA breast cancer whole genomes and performed association analysis with corresponding somatic and germline variants. In our analysis, we identified a subset of patients who harbored a high number of germline TE insertions. Statistical burden testing of germline TE insertions with germline genetic variants (SNPs and Indels), revealed an enrichment of deleterious variants in the NRDE2 and TNKS1BP1 genes. NRDE2 gene involved in the piRNA pathway is known to regulate TEs using RNA silencing whereas, TNKS1BP1 gene is known to be involved in DNA damage repair mechanisms and also helps maintain genomic integrity. Further, patients with high germline TE insertions had a lower median age of diagnosis (top quartile vs bottom 75%, p-value=0.019), suggesting a potential novel role of germline TE insertions in cancer predisposition. Lastly, comparison of somatic TE insertion burdenpattern against somatic tumor mutation burden revealed an inverse correlation, indicating that analysis of TE insertions is critical to breast cancer diagnosis in the clinic. Our results definitively argue that characterization of TEs is essential for elucidating the complete mutational profile of a breast cancer genome. Citation Format: Robin Paul, Milan Radovich, Jeffrey P. Solzak. Transposable element insertions impact the mutational landscape of breast cancer genomes and disease onset [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-303.