L1 Retrotransposon heterogeneity in ovarian tumor cell evolution

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 canc...

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Detalles Bibliográficos
Autores: Nguyen, Thu H.M., Carreira, Patricia E., Sánchez-Luque, Francisco J., Schauer, Stephanie N., Fagg, Allister C., Richardson, Sandra R., Davies, Claire M., Jesuadian, J. Samuel, Kempen, Marie-Jeanne H.C., Troskie, Robin-Lee, James, Cini, Beaven, Elizabeth A., Wallis, Tristan P., Coward, Jermaine I.G., Chetty, Naven P., Crandon, Alexander J., Venter, Deon J., Armes, Jane E., Perrin, Lewis C., Hooper, John D., Ewing, Adam D., Upton, Kyle R., Faulkner, Geoffrey J.
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2018
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/376198
Acceso en línea:http://hdl.handle.net/10261/376198
Access Level:acceso abierto
Palabra clave:Ovarian cancer
Retrotransposon
LINE-1
L1
Chemoresistance
Descripción
Sumario: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.

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