Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma

Ruchi Shukla; Kyle R. Upton; Martin Muñoz-Lopez; Daniel J. Gerhardt; Malcolm E. Fisher; Thu Nguyen; Paul M. Brennan; J. Kenneth Baillie; Agnese Collino; Serena Ghisletti; Shruti Sinha; Fabio Iannelli; Enrico Radaelli; Alexandre Dos Santos; Delphine Rapoud; Catherine Guettier; Didier Samuel; Gioacchino Natoli; Piero Carninci; Francesca D. Ciccarelli; Jose Luis Garcia-Perez; Jamila Faivre; Geoffrey J. Faulkner

doi:10.1016/j.cell.2013.02.032

Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma

Ruchi Shukla, Kyle R. Upton, Martin Muñoz-Lopez, Daniel J. Gerhardt, Malcolm E. Fisher, Thu Nguyen, Paul M. Brennan, J. Kenneth Baillie, Agnese Collino, Serena Ghisletti, Shruti Sinha, Fabio Iannelli, Enrico Radaelli, Alexandre Dos Santos, Delphine Rapoud, Catherine Guettier, Didier Samuel, Gioacchino Natoli, Piero Carninci, Francesca D. CiccarelliJose Luis Garcia-Perez, Jamila Faivre, Geoffrey J. Faulkner^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

298 Citations (Scopus)

Abstract

LINE-1 (L1) retrotransposons are mobile genetic elements comprising ∼17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2^-/- mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.

Original language	English
Pages (from-to)	101-111
Number of pages	11
Journal	Cell
Volume	153
Issue number	1
DOIs	https://doi.org/10.1016/j.cell.2013.02.032
Publication status	Published - 28 Mar 2013
Externally published	Yes

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Shukla, R., Upton, K. R., Muñoz-Lopez, M., Gerhardt, D. J., Fisher, M. E., Nguyen, T., Brennan, P. M., Baillie, J. K., Collino, A., Ghisletti, S., Sinha, S., Iannelli, F., Radaelli, E., Dos Santos, A., Rapoud, D., Guettier, C., Samuel, D., Natoli, G., Carninci, P., ... Faulkner, G. J. (2013). Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma. Cell, 153(1), 101-111. https://doi.org/10.1016/j.cell.2013.02.032

@article{ec3c7d94bd954abeb7974789b226fb5c,

title = "Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma",

abstract = "LINE-1 (L1) retrotransposons are mobile genetic elements comprising ∼17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2-/- mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.",

author = "Ruchi Shukla and Upton, {Kyle R.} and Martin Mu{\~n}oz-Lopez and Gerhardt, {Daniel J.} and Fisher, {Malcolm E.} and Thu Nguyen and Brennan, {Paul M.} and Baillie, {J. Kenneth} and Agnese Collino and Serena Ghisletti and Shruti Sinha and Fabio Iannelli and Enrico Radaelli and {Dos Santos}, Alexandre and Delphine Rapoud and Catherine Guettier and Didier Samuel and Gioacchino Natoli and Piero Carninci and Ciccarelli, {Francesca D.} and Garcia-Perez, {Jose Luis} and Jamila Faivre and Faulkner, {Geoffrey J.}",

note = "Funding Information: We thank Professor Haig Kazazian, Professor Bert Vogelstein, Dr. Bruno Amati, and Dr. Alister Funnell for helpful discussion. We thank Professor Daniel Azoulay, Professor Denis Castaing, Professor Ren{\'e} Adam and Dr. Eric Vibert (Centre H{\'e}patobiliaire, Villejuif), and the Tissue Biobank Group (AP-HP and Universit{\'e} Paris-Sud) for providing HCC specimens. We thank Dr. Christine Beck and Professor John Moran for providing the genomic coordinates of a recently published full-length L1 insertion cohort ( Beck et al., 2010 ). Research performed in the laboratories of D.S., G.N., P.C., F.D.C., J.F., and G.J.F. was funded by the European Union{\textquoteright}s Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 259743 underpinning the MODHEP consortium. J.K.B. and P.M.B. were supported by Wellcome Trust Clinical Fellowships (090385/Z/09/Z and 090386/Z/09/Z, respectively) through the Edinburgh Clinical Academic Track (ECAT). J.L.G.P was supported by FP7-PEOPLE-2007-4-3-IRG, CICE-FEDER-P09-CTS-4980, PeS-FEDER-PI-002, FIS-FEDER-PI11/01489, and the Howard Hughes Medical Institute (IECS-55007420). J.F. acknowledges the support of the Institut National de la Sant{\'e} et de la Recherche M{\'e}dicale (INSERM), the Association pour la Recherche contre le Cancer (ARC 4866), and the Institut National du Cancer (INCa 2009-PAIR-CHC). G.J.F. acknowledges the support of a New Investigator Award from the British BBSRC (BB/H005935/1) and a C.J. Martin Overseas Based Biomedical Fellowship from the Australian NHMRC (575585). ",

year = "2013",

month = mar,

day = "28",

doi = "10.1016/j.cell.2013.02.032",

language = "English",

volume = "153",

pages = "101--111",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "1",

}

Shukla, R, Upton, KR, Muñoz-Lopez, M, Gerhardt, DJ, Fisher, ME, Nguyen, T, Brennan, PM, Baillie, JK, Collino, A, Ghisletti, S, Sinha, S, Iannelli, F, Radaelli, E, Dos Santos, A, Rapoud, D, Guettier, C, Samuel, D, Natoli, G, Carninci, P, Ciccarelli, FD, Garcia-Perez, JL, Faivre, J & Faulkner, GJ 2013, 'Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma', Cell, vol. 153, no. 1, pp. 101-111. https://doi.org/10.1016/j.cell.2013.02.032

TY - JOUR

T1 - Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma

AU - Shukla, Ruchi

AU - Upton, Kyle R.

AU - Muñoz-Lopez, Martin

AU - Gerhardt, Daniel J.

AU - Fisher, Malcolm E.

AU - Nguyen, Thu

AU - Brennan, Paul M.

AU - Baillie, J. Kenneth

AU - Collino, Agnese

AU - Ghisletti, Serena

AU - Sinha, Shruti

AU - Iannelli, Fabio

AU - Radaelli, Enrico

AU - Dos Santos, Alexandre

AU - Rapoud, Delphine

AU - Guettier, Catherine

AU - Samuel, Didier

AU - Natoli, Gioacchino

AU - Carninci, Piero

AU - Ciccarelli, Francesca D.

AU - Garcia-Perez, Jose Luis

AU - Faivre, Jamila

AU - Faulkner, Geoffrey J.

N1 - Funding Information: We thank Professor Haig Kazazian, Professor Bert Vogelstein, Dr. Bruno Amati, and Dr. Alister Funnell for helpful discussion. We thank Professor Daniel Azoulay, Professor Denis Castaing, Professor René Adam and Dr. Eric Vibert (Centre Hépatobiliaire, Villejuif), and the Tissue Biobank Group (AP-HP and Université Paris-Sud) for providing HCC specimens. We thank Dr. Christine Beck and Professor John Moran for providing the genomic coordinates of a recently published full-length L1 insertion cohort ( Beck et al., 2010 ). Research performed in the laboratories of D.S., G.N., P.C., F.D.C., J.F., and G.J.F. was funded by the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement No. 259743 underpinning the MODHEP consortium. J.K.B. and P.M.B. were supported by Wellcome Trust Clinical Fellowships (090385/Z/09/Z and 090386/Z/09/Z, respectively) through the Edinburgh Clinical Academic Track (ECAT). J.L.G.P was supported by FP7-PEOPLE-2007-4-3-IRG, CICE-FEDER-P09-CTS-4980, PeS-FEDER-PI-002, FIS-FEDER-PI11/01489, and the Howard Hughes Medical Institute (IECS-55007420). J.F. acknowledges the support of the Institut National de la Santé et de la Recherche Médicale (INSERM), the Association pour la Recherche contre le Cancer (ARC 4866), and the Institut National du Cancer (INCa 2009-PAIR-CHC). G.J.F. acknowledges the support of a New Investigator Award from the British BBSRC (BB/H005935/1) and a C.J. Martin Overseas Based Biomedical Fellowship from the Australian NHMRC (575585).

PY - 2013/3/28

Y1 - 2013/3/28

N2 - LINE-1 (L1) retrotransposons are mobile genetic elements comprising ∼17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2-/- mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.

AB - LINE-1 (L1) retrotransposons are mobile genetic elements comprising ∼17% of the human genome. New L1 insertions can profoundly alter gene function and cause disease, though their significance in cancer remains unclear. Here, we applied enhanced retrotransposon capture sequencing (RC-seq) to 19 hepatocellular carcinoma (HCC) genomes and elucidated two archetypal L1-mediated mechanisms enabling tumorigenesis. In the first example, 4/19 (21.1%) donors presented germline retrotransposition events in the tumor suppressor mutated in colorectal cancers (MCC). MCC expression was ablated in each case, enabling oncogenic β-catenin/Wnt signaling. In the second example, suppression of tumorigenicity 18 (ST18) was activated by a tumor-specific L1 insertion. Experimental assays confirmed that the L1 interrupted a negative feedback loop by blocking ST18 repression of its enhancer. ST18 was also frequently amplified in HCC nodules from Mdr2-/- mice, supporting its assignment as a candidate liver oncogene. These proof-of-principle results substantiate L1-mediated retrotransposition as an important etiological factor in HCC.

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U2 - 10.1016/j.cell.2013.02.032

DO - 10.1016/j.cell.2013.02.032

M3 - Article

C2 - 23540693

AN - SCOPUS:84875698271

SN - 0092-8674

VL - 153

SP - 101

EP - 111

JO - Cell

JF - Cell

IS - 1

ER -

Endogenous retrotransposition activates oncogenic pathways in hepatocellular carcinoma

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