Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

PCAWG Structural Variation Working Group; PCAWG Consortium

doi:10.1038/s41588-019-0562-0

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

PCAWG Structural Variation Working Group, PCAWG Consortium

Bar-Ilan University - Azrieli Faculty of Medicine

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

258 Scopus citations

Abstract

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage–fusion–bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.

Original language	English
Pages (from-to)	306-319
Number of pages	14
Journal	Nature Genetics
Volume	52
Issue number	3
DOIs	https://doi.org/10.1038/s41588-019-0562-0
State	Published - 1 Mar 2020

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).

Funding

J.M.C.T. is supported by European Research Council (ERC) Starting Grant 716290 ‘SCUBA CANCERS’, Ramon y Cajal grant RYC-2014-14999 and Spanish Ministry of Economy, Industry and Competitiveness (MINECO) grant SAF2015-66368-P. B.R.-M., E.G.A., M.S.G. and S.Z. are supported by PhD fellowships from Xunta de Galicia (Spain) ED481A-2016/151, ED481A-2017/299, ED481A-2017/306 and ED481A-2018/199, respectively. F.S. was supported by ERC Starting Grant 757700 ‘HYPER-INSIGHT’, MINECO grant BFU2017-89833-P ‘RegioMut’, and further acknowledges institutional funding from the MINECO Severo Ochoa award and from the CERCA Programme of the Catalan Government. Y.S.J. was supported by Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number HI16C2387). A.L.B. is supported by MINECO PhD fellowship BES-2016-078166. M.T. was supported by MINECO grant SAF2015-73916-JIN. R.B. received funding through the National Institutes of Health (U24CA210978 and R01CA188228). M.G.B. received funding through MINECO, AEI, Xunta de Galicia and FEDER (BFU2013-41554-P, BFU2016-78121-P, ED431F 2016/019). N.B. is supported by a My First AIRC grant from the Associazione Italiana Ricerca sul Cancro (number 17658). J.D. is a postdoctoral fellow of the Research Foundation Flanders (FWO) and the European Union’s Horizon 2020 research and innovation program (Marie Skłodowska-Curie grant agreement number 703594-DECODE). K.C. and Z.C. are supported by NIH R01 CA172652 and U41 HG007497. Z.C. is supported by an American Heart Association Institutional Data Fellowship Award (17IF33890015). P.A.W.E. is supported by Cancer Research UK. E.A.L. is supported by K01AG051791. I.M. is supported by Cancer Research UK (C57387/ A21777). F.M. is supported by A.I.L. (Associazione Italiana Contro le Leucemie-Linfomi e Mieloma ONLUS) and by S.I.E.S. (Società Italiana di Ematologia Sperimentale). S.M.W. received funding through a SNSF Early Postdoc Mobility fellowship (P2ELP3_155365) and an EMBO Long-Term Fellowship (ALTF 755-2014). J.W. received funding from the Danish Medical Research Council (DFF-4183-00233). D.C.W. is funded by the Li Ka Shing foundation and the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. J.O.K. is supported by an ERC Starting Grant. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation’s support towards the establishment of The Francis Crick Institute. This work is supported by The Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001202), the UK Medical Research Council (FC001202) and the Wellcome Trust (FC001202). H.H.K. is supported by grants from the National Institute of General Medical Sciences (P50GM107632 and 1R01GM099875). K.H.B. is supported by P50GM107632, R01CA163705 and R01GM124531. This work was supported by the TransTumVar project PN013600. R.C.F. thanks Cancer Research UK Programme Grant for esophageal ICGC, Cambridge BRC and ECMC infrastructure support. This work was supported by the Wellcome Trust grant 09805. We acknowledge the contributions of the many clinical networks across the ICGC and TCGA who provided samples and data to the PCAWG Consortium, and the contributions of the Technical Working Group and the Germline Working Group of the PCAWG Consortium for collation, realignment and harmonized variant calling of the cancer genomes used in this study. We thank the patients and their families for their participation in the individual ICGC and TCGA projects.

Funders	Funder number
Associazione Italiana Contro le Leucemie-Linfomi e Mieloma
CERCA Programme of the Catalan Government
Cancer Research UK
Consellería de Cultura, Educación e Ordenación Universitaria, Xunta de Galicia
H2020 European Research Council
Korea Health Industry Development Institute
Marie Skłodowska-Curie	703594-DECODE
Ministerio de Economía y Competitividad
Ministerio de Educación, Cultura y Deporte
National Institutes of Health
Sundhed og Sygdom, Det Frie Forskningsråd
National Institutes of Health	U24CA210978, R01 CA172652, R01CA188228, U41 HG007497
National Cancer Institute	P30CA016672
National Institute of General Medical Sciences	R01GM124531, 1R01GM099875, PN013600, 09805, P50GM107632, R01CA163705
American Heart Association	17IF33890015
European Molecular Biology Organization	ALTF 755-2014
Li Ka Shing Foundation
Sundhed og Sygdom, Det Frie Forskningsråd	DFF-4183-00233
Wellcome Trust
Francis Crick Institute	FC001202
Horizon 2020 Framework Programme	716290
Medical Research Council
National Institute for Health Research
Cancer Research UK	K01AG051791, C57387/ A21777
European Commission	RYC-2014-14999
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung	P2ELP3_155365
Fonds Wetenschappelijk Onderzoek
Ministerio de Economía y Competitividad	SAF2015-66368-P, SAF2015-73916-JIN
Ministry of Health and Welfare	HI16C2387
Korea Health Industry Development Institute
Associazione Italiana per la Ricerca sul Cancro	17658
Associazione Italiana Contro le Leucemie - Linfomi e Mieloma
European Regional Development Fund	ED431F 2016/019, BFU2016-78121-P, BFU2013-41554-P
Ministerio de Economía, Industria y Competitividad, Gobierno de España
Xunta de Galicia	757700, ED481A-2017/306, BFU2017-89833-P, ED481A-2016/151, ED481A-2018/199, ED481A-2017/299
Agencia Estatal de Investigación

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41588-019-0562-0

Cite this

@article{afd4ec668e2f467e9f62c13e2fb08232,

title = "Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition",

abstract = "About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage–fusion–bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.",

author = "{PCAWG Structural Variation Working Group} and {PCAWG Consortium} and Bernardo Rodriguez-Martin and Alvarez, {Eva G.} and Adrian Baez-Ortega and Jorge Zamora and Fran Supek and Jonas Demeulemeester and Martin Santamarina and Ju, {Young Seok} and Javier Temes and Daniel Garcia-Souto and Harald Detering and Yilong Li and Jorge Rodriguez-Castro and Ana Dueso-Barroso and Bruzos, {Alicia L.} and Dentro, {Stefan C.} and Blanco, {Miguel G.} and Gianmarco Contino and Daniel Ardeljan and Marta Tojo and Roberts, {Nicola D.} and Sonia Zumalave and Edwards, {Paul A.} and Joachim Weischenfeldt and Montserrat Puiggr{\`o}s and Zechen Chong and Ken Chen and Lee, {Eunjung Alice} and Wala, {Jeremiah A.} and Raine, {Keiran M.} and Adam Butler and Waszak, {Sebastian M.} and Navarro, {Fabio C.P.} and Schumacher, {Steven E.} and Jean Monlong and Francesco Maura and Niccolo Bolli and Guillaume Bourque and Mark Gerstein and Park, {Peter J.} and Wedge, {David C.} and Rameen Beroukhim and David Torrents and Korbel, {Jan O.} and I{\~n}igo Martincorena and Fitzgerald, {Rebecca C.} and {Van Loo}, Peter and Kazazian, {Haig H.} and Burns, {Kathleen H.} and Milana Frenkel-Morgenstern",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = mar,

day = "1",

doi = "10.1038/s41588-019-0562-0",

language = "אנגלית",

volume = "52",

pages = "306--319",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "3",

}

TY - JOUR

T1 - Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

AU - PCAWG Structural Variation Working Group

AU - PCAWG Consortium

AU - Rodriguez-Martin, Bernardo

AU - Alvarez, Eva G.

AU - Baez-Ortega, Adrian

AU - Zamora, Jorge

AU - Supek, Fran

AU - Demeulemeester, Jonas

AU - Santamarina, Martin

AU - Ju, Young Seok

AU - Temes, Javier

AU - Garcia-Souto, Daniel

AU - Detering, Harald

AU - Li, Yilong

AU - Rodriguez-Castro, Jorge

AU - Dueso-Barroso, Ana

AU - Bruzos, Alicia L.

AU - Dentro, Stefan C.

AU - Blanco, Miguel G.

AU - Contino, Gianmarco

AU - Ardeljan, Daniel

AU - Tojo, Marta

AU - Roberts, Nicola D.

AU - Zumalave, Sonia

AU - Edwards, Paul A.

AU - Weischenfeldt, Joachim

AU - Puiggròs, Montserrat

AU - Chong, Zechen

AU - Chen, Ken

AU - Lee, Eunjung Alice

AU - Wala, Jeremiah A.

AU - Raine, Keiran M.

AU - Butler, Adam

AU - Waszak, Sebastian M.

AU - Navarro, Fabio C.P.

AU - Schumacher, Steven E.

AU - Monlong, Jean

AU - Maura, Francesco

AU - Bolli, Niccolo

AU - Bourque, Guillaume

AU - Gerstein, Mark

AU - Park, Peter J.

AU - Wedge, David C.

AU - Beroukhim, Rameen

AU - Torrents, David

AU - Korbel, Jan O.

AU - Martincorena, Iñigo

AU - Fitzgerald, Rebecca C.

AU - Van Loo, Peter

AU - Kazazian, Haig H.

AU - Burns, Kathleen H.

AU - Frenkel-Morgenstern, Milana

PY - 2020/3/1

Y1 - 2020/3/1

N2 - About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage–fusion–bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.

AB - About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage–fusion–bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.

UR - http://www.scopus.com/inward/record.url?scp=85079062163&partnerID=8YFLogxK

U2 - 10.1038/s41588-019-0562-0

DO - 10.1038/s41588-019-0562-0

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 32024998

AN - SCOPUS:85079062163

SN - 1061-4036

VL - 52

SP - 306

EP - 319

JO - Nature Genetics

JF - Nature Genetics

IS - 3

ER -

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition

Abstract

Bibliographical note

Funding

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this