Abstract B27: The use of mouse models for understanding the in vivo impact of cancer-relevant genetic defects on genomic instability induced by human LINE-1 retrotransposon

Abstract

Abstract Purpose: The human retrotransposon Long Interspersed Element 1 (L1) can contribute to genomic instability through de novo retrotransposition events, some of which could be mutagenic. L1 has long been considered to have a role in a variety of human diseases driven by genomic instability, most notably cancer. Second-generation sequencing approaches demonstrated that many human cancers harbor numerous de novo L1 inserts. While these data reinforce the concept that L1-associated genomic instability and cancer are probably intertwined, direct experimental evidence establishing this connection and, importantly, the understanding of the circumstances underlying L1 contribution to the disease are missing. The lack of this knowledge is in part due to the shortage of mammalian models suitable for testing these hypotheses. Methods: We have developed a custom mouse model of human L1 retrotransposition by introducing a single copy of the human L1 transgene into the mouse genome using homologous recombination. Using this L1 transgenic model, the existing mouse models of human cancer, and a custom quantitative droplet digital PCR assay for measuring de novo mobilization of the human L1 transgene, we have investigated the impact of genetic defects in two DNA-repair pathways on accumulation of the L1 transgene-induced genomic instability in somatic tissues in vivo. Results: Our data demonstrate that all tested mouse organs support de novo L1 retrotransposition events. The occurrence of these events is stochastic as there is significant individual variation among transgenic mice. Our data also demonstrate that both tested genetic defects promote L1 retrotransposition in vivo in a dose-dependent manner as demonstrated by the comparison of L1 mobilization between the wild-type mice and mice hetero- or homozygous for the defect. Conclusions: The development of the custom transgenic mouse model of human L1 retrotransposition has allowed us to determine that a loss of function of a single DNA-repair gene is sufficient to increase L1-induced genomic instability in somatic mammalian tissues. These findings provide important proof-of-principle results that tumor-specific DNA-repair defects impact L1 retrotransposition in mammalian tissues in vivo. These findings also provide critical insights as to when accumulation of L1 damage may take place during tumorigenesis. These findings have important implications for cancer patients because they suggest that tumor-specific DNA-repair defects may influence the amount of genomic instability associated with DNA damage from L1 elements in vivo. Ongoing results will be discussed. Citation Format: Dawn deHaro, Claiborne M. Christian, T. May Chynces, Mark Sokolowski, Victoria P. Belancio. The use of mouse models for understanding the in vivo impact of cancer-relevant genetic defects on genomic instability induced by human LINE-1 retrotransposon [abstract]. In: Proceedings of the AACR Special Conference: Advances in Modeling Cancer in Mice: Technology, Biology, and Beyond; 2017 Sep 24-27; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(10 Suppl):Abstract nr B27.