L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution
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 ova...
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| Format: | Article |
| Language: | English |
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Elsevier
2018-06-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124718308714 |
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doaj-02b2c6ba831b4bec8988f6149861dbe1 |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Thu H.M. Nguyen Patricia E. Carreira Francisco J. Sanchez-Luque Stephanie N. Schauer Allister C. Fagg Sandra R. Richardson Claire M. Davies J. Samuel Jesuadian Marie-Jeanne H.C. Kempen Robin-Lee Troskie Cini James Elizabeth A. Beaven Tristan P. Wallis Jermaine I.G. Coward Naven P. Chetty Alexander J. Crandon Deon J. Venter Jane E. Armes Lewis C. Perrin John D. Hooper Adam D. Ewing Kyle R. Upton Geoffrey J. Faulkner |
| spellingShingle |
Thu H.M. Nguyen Patricia E. Carreira Francisco J. Sanchez-Luque Stephanie N. Schauer Allister C. Fagg Sandra R. Richardson Claire M. Davies J. Samuel Jesuadian Marie-Jeanne H.C. Kempen Robin-Lee Troskie Cini James Elizabeth A. Beaven Tristan P. Wallis Jermaine I.G. Coward Naven P. Chetty Alexander J. Crandon Deon J. Venter Jane E. Armes Lewis C. Perrin John D. Hooper Adam D. Ewing Kyle R. Upton Geoffrey J. Faulkner L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution Cell Reports |
| author_facet |
Thu H.M. Nguyen Patricia E. Carreira Francisco J. Sanchez-Luque Stephanie N. Schauer Allister C. Fagg Sandra R. Richardson Claire M. Davies J. Samuel Jesuadian Marie-Jeanne H.C. Kempen Robin-Lee Troskie Cini James Elizabeth A. Beaven Tristan P. Wallis Jermaine I.G. Coward Naven P. Chetty Alexander J. Crandon Deon J. Venter Jane E. Armes Lewis C. Perrin John D. Hooper Adam D. Ewing Kyle R. Upton Geoffrey J. Faulkner |
| author_sort |
Thu H.M. Nguyen |
| title |
L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution |
| title_short |
L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution |
| title_full |
L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution |
| title_fullStr |
L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution |
| title_full_unstemmed |
L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell Evolution |
| title_sort |
l1 retrotransposon heterogeneity in ovarian tumor cell evolution |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2018-06-01 |
| description |
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 |
| url |
http://www.sciencedirect.com/science/article/pii/S2211124718308714 |
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doaj-02b2c6ba831b4bec8988f6149861dbe12020-11-25T01:09:28ZengElsevierCell Reports2211-12472018-06-01231337303740L1 Retrotransposon Heterogeneity in Ovarian Tumor Cell EvolutionThu H.M. Nguyen0Patricia E. Carreira1Francisco J. Sanchez-Luque2Stephanie N. Schauer3Allister C. Fagg4Sandra R. Richardson5Claire M. Davies6J. Samuel Jesuadian7Marie-Jeanne H.C. Kempen8Robin-Lee Troskie9Cini James10Elizabeth A. Beaven11Tristan P. Wallis12Jermaine I.G. Coward13Naven P. Chetty14Alexander J. Crandon15Deon J. Venter16Jane E. Armes17Lewis C. Perrin18John D. Hooper19Adam D. Ewing20Kyle R. Upton21Geoffrey J. Faulkner22Mater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia; Pfizer-University of Granada-Andalusian Government Centre for Genomics and Oncological Research, PT Ciencias de la Salud, Granada 18016, SpainMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Health Services, South Brisbane, QLD 4101, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Health Services, South Brisbane, QLD 4101, AustraliaMater Health Services, South Brisbane, QLD 4101, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia; Mater Health Services, South Brisbane, QLD 4101, AustraliaMater Health Services, South Brisbane, QLD 4101, AustraliaMater Health Services, South Brisbane, QLD 4101, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia; Mater Health Services, South Brisbane, QLD 4101, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia; Mater Health Services, South Brisbane, QLD 4101, AustraliaMater Health Services, South Brisbane, QLD 4101, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, AustraliaMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia; School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, QLD 4072, Australia; Corresponding authorMater Research Institute, University of Queensland, TRI Building, Woolloongabba, QLD 4102, Australia; Queensland Brain Institute, University of Queensland, Brisbane, QLD 4072, Australia; Corresponding authorSummary: 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, chemoresistancehttp://www.sciencedirect.com/science/article/pii/S2211124718308714 |