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

被引：222

作者：

Rodriguez-Martin, Bernardo ^{[1
,2
,3
,44
]}

Alvarez, Eva G. ^{[1
,2
,3
,44
]}

Baez-Ortega, Adrian ^{[4
]}

Zamora, Jorge ^{[1
,2
,3
,44
,57
]}

Supek, Fran ^{[5
,6
]}

Demeulemeester, Jonas ^{[7
,8
]}

Santamarina, Martin ^{[1
,2
,3
]}

Ju, Young Seok ^{[9
,10
,57
,77
]}

Temes, Javier ^{[1
]}

Garcia-Souto, Daniel ^{[1
]}

Detering, Harald ^{[3
,11
,12
]}

Li, Yilong ^{[10
,57
]}

Rodriguez-Castro, Jorge ^{[1
]}

Dueso-Barroso, Ana ^{[13
,14
,61
]}

Bruzos, Alicia L. ^{[1
,2
,3
]}

Dentro, Stefan C. ^{[7
,15
,16
]}

Blanco, Miguel G. ^{[17
,18
]}

Contino, Gianmarco ^{[19
]}

Ardeljan, Daniel ^{[20
]}

Tojo, Marta ^{[11
]}

Roberts, Nicola D. ^{[10
,57
]}

Zumalave, Sonia ^{[1
,2
]}

Edwards, Paul A. W. ^{[21
,22
]}

Weischenfeldt, Joachim ^{[23
,24
,25
,107
,108
,110
]}

Puiggros, Montserrat ^{[13
,61
]}

Chong, Zechen ^{[26
,27
,28
]}

Chen, Ken ^{[26
,43
]}

Lee, Eunjung Alice ^{[29
,30
]}

Wala, Jeremiah A. ^{[30
,31
,32
,45
,46
,91
]}

Raine, Keiran ^{[10
]}

Butler, Adam ^{[10
]}

Waszak, Sebastian M. ^{[25
]}

Navarro, Fabio C. P. ^{[33
,34
,35
]}

Schumacher, Steven E. ^{[30
,31
,32
]}

Monlong, Jean ^{[36
]}

Maura, Francesco ^{[10
,37
,38
]}

Bolli, Niccolo ^{[37
,38
]}

Bourque, Guillaume ^{[36
]}

Gerstein, Mark ^{[33
,34
,35
,66
]}

Park, Peter J. ^{[39
]}

Wedge, David C. ^{[10
,16
,40
]}

Beroukhim, Rameen ^{[30
,31
,32
]}

Torrents, David ^{[6
,13
,61
]}

Korbel, Jan O. ^{[25
,84
]}

Martincorena, Inigo ^{[10
]}

Fitzgerald, Rebecca C. ^{[19
]}

Van Loo, Peter ^{[7
,8
]}

Kazazian, Haig H. ^{[20
]}

Burns, Kathleen H. ^{[10
,20
,41
,42
,56
,57
]}

Campbell, Peter J. ^{[10
,42
,57
]}

机构：

[1] Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis CIMUS, Genomes & Dis, Santiago De Compostela, Spain

[2] Univ Santiago de Compostela, Dept Zool Genet & Phys Anthropol, Santiago De Compostela, Spain

[3] Univ Vigo, Biomed Res Ctr CINBIO, Vigo, Spain

[4] Univ Cambridge, Dept Vet Med, Transmissible Canc Grp, Cambridge, England

[5] Barcelona Inst Sci & Technol, Inst Res Biomed IRB Barcelona, Genome Data Sci, Barcelona, Spain

[6] ICREA, Barcelona, Spain

[7] Francis Crick Inst, London, England

[8] Univ Leuven, Dept Human Genet, Leuven, Belgium

[9] Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea

[10] Wellcome Sanger Inst, Canc Ageing & Somat Mutat Programme, Cambridge, England

[11] Univ Vigo, Dept Biochem Genet & Immunol, Vigo, Spain

[12] Galicia Hlth Res Inst, Vigo, Spain

[13] CNS, BSC, Barcelona, Spain

[14] Univ Vic, Fac Sci & Technol, Cent Univ Catalonia UVic UCC, Vic, Spain

[15] Wellcome Sanger Inst, Expt Canc Genet, Cambridge, England

[16] Univ Oxford, Oxford Big Data Inst, Oxford, England

[17] Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis CIMUS, DNA Repair & Genome Integr, Santiago De Compostela, Spain

[18] Univ Santiago de Compostela, Dept Biochem & Mol Biol, Santiago De Compostela, Spain

[19] Univ Cambridge, MRC, Canc Unit, Cambridge, England

[20] Johns Hopkins Univ, Dept Genet Med, Sch Med, Baltimore, MD USA

[21] Univ Cambridge, Dept Pathol, Cambridge, England

[22] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge, England

[23] Univ Copenhagen, Biotech Res & Innovat Ctr, Copenhagen, Denmark

[24] Rigshosp, Finsen Lab, Copenhagen, Denmark

[25] European Mol Biol Lab, Genome Biol Unit, Heidelberg, Germany

[26] Univ Texas MD Anderson Canc Ctr, Dept Bioinformat & Computat Biol, Houston, TX 77030 USA

[27] Univ Alabama Birmingham, Sch Med, Dept Genet, Birmingham, AL USA

[28] Univ Alabama Birmingham, Sch Med, Informat Inst, Birmingham, AL USA

[29] Harvard Med Sch, Boston Childrens Hosp, Div Genet & Genom, Boston, MA 02115 USA

[30] Broad Inst Harvard & MIT, Cambridge, MA USA

[31] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02115 USA

[32] Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

[33] Yale Univ, Program Computat Biol & Bioinformat, New Haven, CT USA

[34] Yale Univ, Dept Mol Biophys & Biochem, New Haven, CT USA

[35] Yale Univ, Dept Comp Sci, POB 2158, New Haven, CT 06520 USA

[36] McGill Univ, Dept Human Genet, Montreal, PQ, Canada

[37] Univ Milan, Dept Oncol & Onco Hematol, Milan, Italy

[38] Fdn IRCCS Ist Nazl Tumori, Dept Med Oncol & Hematol, Milan, Italy

[39] Harvard Med Sch, Dept Biomed Informat, Boston, MA 02115 USA

[40] Oxford NIHR Biomed Res Ctr, Oxford, England

[41] Johns Hopkins Univ, Sch Med, Dept Pathol, Baltimore, MD 21205 USA

[42] Univ Cambridge, Dept Haematol, Cambridge, England

[43] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[44] Univ Santiago de Compostela, Ctr Res Mol Med & Chron Dis CIMUS, Santiago De Compostela, Spain

[45] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[46] Harvard Med Sch, Boston, MA 02115 USA

[47] Ontario Inst Canc Res, Computat Biol Program, Toronto, ON, Canada

[48] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[49] Univ Toronto, Dept Pharmacol, Toronto, ON, Canada

[50] Univ Calif Los Angeles, Los Angeles, CA USA

来源：

NATURE GENETICS | 2020年 / 52卷 / 03期

基金：

欧洲研究理事会; 英国惠康基金; 瑞士国家科学基金会; 美国国家卫生研究院; 英国医学研究理事会;

关键词：

L1; RETROTRANSPOSITION; SOMATIC RETROTRANSPOSITION; READ ALIGNMENT; ELEMENTS; DNA; INSTABILITY; LANDSCAPE; DELETION;

D O I：

10.1038/s41588-019-0562-0

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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. An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

引用

页码：306 / +

页数：17

共 50 条

[1] Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition
Bernardo Rodriguez-Martin
Eva G. Alvarez
Adrian Baez-Ortega
Jorge Zamora
Fran Supek
Jonas Demeulemeester
Martin Santamarina
Young Seok Ju
Javier Temes
Daniel Garcia-Souto
Harald Detering
Yilong Li
Jorge Rodriguez-Castro
Ana Dueso-Barroso
Alicia L. Bruzos
Stefan C. Dentro
Miguel G. Blanco
Gianmarco Contino
Daniel Ardeljan
Marta Tojo
Nicola D. Roberts
Sonia Zumalave
Paul A. Edwards
Joachim Weischenfeldt
Montserrat Puiggròs
Zechen Chong
Ken Chen
Eunjung Alice Lee
Jeremiah A. Wala
Keiran M. Raine
Adam Butler
Sebastian M. Waszak
Fabio C. P. Navarro
Steven E. Schumacher
Jean Monlong
Francesco Maura
Niccolo Bolli
Guillaume Bourque
Mark Gerstein
Peter J. Park
David C. Wedge
Rameen Beroukhim
David Torrents
Jan O. Korbel
Iñigo Martincorena
Rebecca C. Fitzgerald
Peter Van Loo
Haig H. Kazazian
Kathleen H. Burns
Peter J. Campbell
[J]. Nature Genetics, 2020, 52 : 306 - 319
[2] Author Correction: Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition
Bernardo Rodriguez-Martin
Eva G. Alvarez
Adrian Baez-Ortega
Jorge Zamora
Fran Supek
Jonas Demeulemeester
Martin Santamarina
Young Seok Ju
Javier Temes
Daniel Garcia-Souto
Harald Detering
Yilong Li
Jorge Rodriguez-Castro
Ana Dueso-Barroso
Alicia L. Bruzos
Stefan C. Dentro
Miguel G. Blanco
Gianmarco Contino
Daniel Ardeljan
Marta Tojo
Nicola D. Roberts
Sonia Zumalave
Paul A. Edwards
Joachim Weischenfeldt
Montserrat Puiggròs
Zechen Chong
Ken Chen
Eunjung Alice Lee
Jeremiah A. Wala
Keiran M. Raine
Adam Butler
Sebastian M. Waszak
Fabio C. P. Navarro
Steven E. Schumacher
Jean Monlong
Francesco Maura
Niccolo Bolli
Guillaume Bourque
Mark Gerstein
Peter J. Park
David C. Wedge
Rameen Beroukhim
David Torrents
Jan O. Korbel
Iñigo Martincorena
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Peter Van Loo
Haig H. Kazazian
Kathleen H. Burns
Peter J. Campbell
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Alvarez, Eva G.
Baez-Ortega, Adrian
Zamora, Jorge
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Demeulemeester, Jonas
Santamarina, Martin
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Temes, Javier
Garcia-Souto, Daniel
Detering, Harald
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Rodriguez-Castro, Jorge
Dueso-Barroso, Ana
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Dentro, Stefan C.
Blanco, Miguel G.
Contino, Gianmarco
Ardeljan, Daniel
Tojo, Marta
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Zumalave, Sonia
Edwards, Paul A.
Weischenfeldt, Joachim
Puiggros, Montserrat
Chong, Zechen
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Raine, Keiran M.
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Maura, Francesco
Bolli, Niccolo
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Park, Peter J.
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Torrents, David
Korbel, Jan O.
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Fitzgerald, Rebecca C.
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[4] Pan-cancer analysis of whole genomes
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Zhang, Junjun
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