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.W.
AU - Weischenfeldt, Joachim
AU - Puiggròs, Montserrat
AU - Chong, Zechen
AU - Chen, Ken
AU - Lee, Eunjung Alice
AU - Wala, Jeremiah A.
AU - Raine, Keiran
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, Inigo
AU - Fitzgerald, Rebecca C.
AU - Van Loo, Peter
AU - Kazazian, Haig H.
AU - Burns, Kathleen H.
AU - Campbell, Peter J.
AU - Tubio, Jose M.C.
AU - Lynch, Andy G.
N1 - 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.
PY - 2020/3
Y1 - 2020/3
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.
KW - Cancer
KW - Genomics
U2 - 10.1038/s41588-019-0562-0
DO - 10.1038/s41588-019-0562-0
M3 - Article
C2 - 32024998
AN - SCOPUS:85079062163
SN - 1061-4036
VL - 52
SP - 306
EP - 319
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -
