Using transposon elements to elucidate the genetic mechanisms of HCC-associated lung metastases

Abstract Metastases account for most cancer-related deaths as a result of primary cancer spreading to distant sites. Amongst human hepatocellular carcinoma (HCC), there is a drastic decrease in the survival rate observed in patients with early stage localized HCC to late stage metastasis-associated HCC. Importantly, the genetic mechanisms associated with metastasis-associated HCC remains elusive. Therefore, a forward genetic screen in mice using Sleeping Beauty (SB) insertional mutagenesis system was developed to identify genes associated with metastasis-associated HCC. Truncated version of the epidermal growth factor receptor (Egfr) gene was frequently detected in both mouse primary liver tumors and lung metastases, which was confirmed by DNA sequencing and RNA sequencing. This indicates the importance of Egfr mutations for liver tumorigenesis and the metastasis process. More importantly, additional candidate genes involved in the metastasis process were also identified by our forward genetic screen and showed to be relevant in human HCC patients at the M1 cancer metastasis stage. Taken together, our study shows that the SB screen yields a high fraction of relevant events in human liver cancer and can provide valuable information on the evolution of metastasis-associated HCC. The authors declare that they have no competing interests. Citation Format: Lilian H. Lo, Amy P. Chiu, Xiao-Xiao Li, Barbara R. Tschida, Dewi K. Rowlands, David A. Largaespada, Vincent W. Keng. Using transposon elements to elucidate the genetic mechanisms of HCC-associated lung metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5183.