L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution

Abstract

Summary: LINE-1 (L1) retrotransposons are a source of insertional mutagenesis in tumor cells. However, the clinical significance of L1 mobilization during tumorigenesis remains unclear. Here, we applied retrotransposon capture sequencing (RC-seq) to multiple single-cell clones isolated from five ovarian cancer cell lines and HeLa cells and detected endogenous L1 retrotransposition in vitro. We then applied RC-seq to ovarian tumor and matched blood samples from 19 patients and identified 88 tumor-specific L1 insertions. In one tumor, an intronic de novo L1 insertion supplied a novel cis-enhancer to the putative chemoresistance gene STC1. Notably, the tumor subclone carrying the STC1 L1 mutation increased in prevalence after chemotherapy, further increasing STC1 expression. We also identified hypomethylated donor L1s responsible for new L1 insertions in tumors and cultivated cancer cells. These congruent in vitro and in vivo results highlight L1 insertional mutagenesis as a common component of ovarian tumorigenesis and cancer genome heterogeneity. : Acquired chemoresistance drives ovarian cancer mortality. Nguyen et al. show that L1 retrotransposons, a type of mobile genetic element, can escape silencing in ovarian tumor cells. They find a tumor-specific L1 insertion that enhances STC1 oncogene expression and is selected for during chemotherapy. L1-driven chemoresistance may therefore affect clinical outcomes. Keywords: ovarian cancer, retrotransposon, LINE-1, L1, chemoresistance