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

B. Rodriguez-Martin; E.G. Alvarez; A. Baez-Ortega; J. Zamora; F. Supek; J. Demeulemeester; M. Santamarina; Y.S. Ju; J. Temes; D. Garcia-Souto; H. Detering; Y. Li; J. Rodriguez-Castro; A. Dueso-Barroso; A.L. Bruzos; S.C. Dentro; M.G. Blanco; G. Contino; D. Ardeljan; M. Tojo; N.D. Roberts; S. Zumalave; P.A. Edwards; J. Weischenfeldt; M. Puiggròs; Z. Chong; K. Chen; E.A. Lee; J.A. Wala; K. Raine; A. Butler; S.M. Waszak; F.C.P. Navarro; S.E. Schumacher; J. Monlong; F. Maura; N. Bolli; G. Bourque; M. Gerstein; P.J. Park; D.C. Wedge; R. Beroukhim; D. Torrents; J.O. Korbel; I. Martincorena; R.C. Fitzgerald; P. Van Loo; H.H. Kazazian; K.H. Burns; K.C. Akdemir; E.G. Alvarez; A. Baez-Ortega; R. Beroukhim; P.C. Boutros; D.D.L. Bowtell; B. Brors; K.H. Burns; P.J. Campbell; K. Chan; K. Chen; I. Cortés-Ciriano; A. Dueso-Barroso; A.J. Dunford; P.A. Edwards; X. Estivill; D. Etemadmoghadam; L. Feuerbach; J.L. Fink; M. Frenkel-Morgenstern; D.W. Garsed; M. Gerstein; D.A. Gordenin; D. Haan; J.E. Haber; J.M. Hess; B. Hutter; M. Imielinski; D.T.W. Jones; Y.S. Ju; M.D. Kazanov; L.J. Klimczak; Y. Koh; J.O. Korbel; K. Kumar; E.A. Lee; J.J.-K. Lee; Y. Li; A.G. Lynch; G. Macintyre; F. Markowetz; I. Martincorena; A. Martinez-Fundichely; M. Meyerson; S. Miyano; H. Nakagawa; F.C.P. Navarro; S. Ossowski; P.J. Park; J.V. Pearson; M. Puiggròs; K. Rippe; N.D. Roberts; S.A. Roberts; B. Rodriguez-Martin; S.E. Schumacher; R. Scully; M. Shackleton; N. Sidiropoulos; L. Sieverling; C. Stewart; D. Torrents; J.M.C. Tubio; I. Villasante; N. Waddell; J.A. Wala; J. Weischenfeldt; L. Yang; X. Yao; S.-S. Yoon; J. Zamora; C.-Z. Zhang; P.J. Campbell; J.M.C. Tubio

doi:10.1038/s41588-019-0562-0

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

B. Rodriguez-Martin, E.G. Alvarez, A. Baez-Ortega, J. Zamora, F. Supek, J. Demeulemeester, M. Santamarina, Y.S. Ju, J. Temes, D. Garcia-Souto, H. Detering, Y. Li, J. Rodriguez-Castro, A. Dueso-Barroso, A.L. Bruzos, S.C. Dentro, M.G. Blanco, G. Contino, D. Ardeljan, M. TojoN.D. Roberts, S. Zumalave, P.A. Edwards, J. Weischenfeldt, M. Puiggròs, Z. Chong, K. Chen, E.A. Lee, J.A. Wala, K. Raine, A. Butler, S.M. Waszak, F.C.P. Navarro, S.E. Schumacher, J. Monlong, F. Maura, N. Bolli, G. Bourque, M. Gerstein, P.J. Park, D.C. Wedge, R. Beroukhim, D. Torrents, J.O. Korbel, I. Martincorena, R.C. Fitzgerald, P. Van Loo, H.H. Kazazian, K.H. Burns, K.C. Akdemir, E.G. Alvarez, A. Baez-Ortega, R. Beroukhim, P.C. Boutros, D.D.L. Bowtell, B. Brors, K.H. Burns, P.J. Campbell, K. Chan, K. Chen, I. Cortés-Ciriano, A. Dueso-Barroso, A.J. Dunford, P.A. Edwards, X. Estivill, D. Etemadmoghadam, L. Feuerbach, J.L. Fink, M. Frenkel-Morgenstern, D.W. Garsed, M. Gerstein, D.A. Gordenin, D. Haan, J.E. Haber, J.M. Hess, B. Hutter, M. Imielinski, D.T.W. Jones, Y.S. Ju, M.D. Kazanov, L.J. Klimczak, Y. Koh, J.O. Korbel, K. Kumar, E.A. Lee, J.J.-K. Lee, Y. Li, A.G. Lynch, G. Macintyre, F. Markowetz, I. Martincorena, A. Martinez-Fundichely, M. Meyerson, S. Miyano, H. Nakagawa, F.C.P. Navarro, S. Ossowski, P.J. Park, J.V. Pearson, M. Puiggròs, K. Rippe, N.D. Roberts, S.A. Roberts, B. Rodriguez-Martin, S.E. Schumacher, R. Scully, M. Shackleton, N. Sidiropoulos, L. Sieverling, C. Stewart, D. Torrents, J.M.C. Tubio, I. Villasante, N. Waddell, J.A. Wala, J. Weischenfeldt, L. Yang, X. Yao, S.-S. Yoon, J. Zamora, C.-Z. Zhang, P.J. Campbell, J.M.C. Tubio

Division of Cancer Sciences (L5)

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

123 Downloads (Pure)

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
Early online date	5 Feb 2020
DOIs	https://doi.org/10.1038/s41588-019-0562-0
Publication status	Published - 1 Mar 2020

Keywords

Carcinogenesis/genetics
Gene Rearrangement/genetics
Genome, Human/genetics
Humans
Long Interspersed Nucleotide Elements/genetics
Neoplasms/genetics
Retroelements/genetics

Research Beacons, Institutes and Platforms

Manchester Cancer Research Centre

UN SDGs

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

Access to Document

10.1038/s41588-019-0562-0Licence: CC BY

s41586-020-1969-6Final published version, 22.6 MBLicence: CC BY

Cite this

Rodriguez-Martin, B., Alvarez, E. G., Baez-Ortega, A., Zamora, J., Supek, F., Demeulemeester, J., Santamarina, M., Ju, Y. S., Temes, J., Garcia-Souto, D., Detering, H., Li, Y., Rodriguez-Castro, J., Dueso-Barroso, A., Bruzos, A. L., Dentro, S. C., Blanco, M. G., Contino, G., Ardeljan, D., ... Tubio, J. M. C. (2020). Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition. Nature Genetics, 52(3), 306-319. https://doi.org/10.1038/s41588-019-0562-0

@article{5dd21615a2ad4f83ac4b8dd99881dd10,

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.",

keywords = "Carcinogenesis/genetics, Gene Rearrangement/genetics, Genome, Human/genetics, Humans, Long Interspersed Nucleotide Elements/genetics, Neoplasms/genetics, Retroelements/genetics",

author = "B. Rodriguez-Martin and E.G. Alvarez and A. Baez-Ortega and J. Zamora and F. Supek and J. Demeulemeester and M. Santamarina and Y.S. Ju and J. Temes and D. Garcia-Souto and H. Detering and Y. Li and J. Rodriguez-Castro and A. Dueso-Barroso and A.L. Bruzos and S.C. Dentro and M.G. Blanco and G. Contino and D. Ardeljan and M. Tojo and N.D. Roberts and S. Zumalave and P.A. Edwards and J. Weischenfeldt and M. Puiggr{\`o}s and Z. Chong and K. Chen and E.A. Lee and J.A. Wala and K. Raine and A. Butler and S.M. Waszak and F.C.P. Navarro and S.E. Schumacher and J. Monlong and F. Maura and N. Bolli and G. Bourque and M. Gerstein and P.J. Park and D.C. Wedge and R. Beroukhim and D. Torrents and J.O. Korbel and I. Martincorena and R.C. Fitzgerald and {Van Loo}, P. and H.H. Kazazian and K.H. Burns and K.C. Akdemir and E.G. Alvarez and A. Baez-Ortega and R. Beroukhim and P.C. Boutros and D.D.L. Bowtell and B. Brors and K.H. Burns and P.J. Campbell and K. Chan and K. Chen and I. Cort{\'e}s-Ciriano and A. Dueso-Barroso and A.J. Dunford and P.A. Edwards and X. Estivill and D. Etemadmoghadam and L. Feuerbach and J.L. Fink and M. Frenkel-Morgenstern and D.W. Garsed and M. Gerstein and D.A. Gordenin and D. Haan and J.E. Haber and J.M. Hess and B. Hutter and M. Imielinski and D.T.W. Jones and Y.S. Ju and M.D. Kazanov and L.J. Klimczak and Y. Koh and J.O. Korbel and K. Kumar and E.A. Lee and J.J.-K. Lee and Y. Li and A.G. Lynch and G. Macintyre and F. Markowetz and I. Martincorena and A. Martinez-Fundichely and M. Meyerson and S. Miyano and H. Nakagawa and F.C.P. Navarro and S. Ossowski and P.J. Park and J.V. Pearson and M. Puiggr{\`o}s and K. Rippe and N.D. Roberts and S.A. Roberts and B. Rodriguez-Martin and S.E. Schumacher and R. Scully and M. Shackleton and N. Sidiropoulos and L. Sieverling and C. Stewart and D. Torrents and J.M.C. Tubio and I. Villasante and N. Waddell and J.A. Wala and J. Weischenfeldt and L. Yang and X. Yao and S.-S. Yoon and J. Zamora and C.-Z. Zhang and P.J. Campbell and J.M.C. Tubio",

year = "2020",

month = mar,

day = "1",

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

language = "English",

volume = "52",

pages = "306--319",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Springer Nature",

number = "3",

}

Rodriguez-Martin, B, Alvarez, EG, Baez-Ortega, A, Zamora, J, Supek, F, Demeulemeester, J, Santamarina, M, Ju, YS, Temes, J, Garcia-Souto, D, Detering, H, Li, Y, Rodriguez-Castro, J, Dueso-Barroso, A, Bruzos, AL, Dentro, SC, Blanco, MG, Contino, G, Ardeljan, D, Tojo, M, Roberts, ND, Zumalave, S, Edwards, PA, Weischenfeldt, J, Puiggròs, M, Chong, Z, Chen, K, Lee, EA, Wala, JA, Raine, K, Butler, A, Waszak, SM, Navarro, FCP, Schumacher, SE, Monlong, J, Maura, F, Bolli, N, Bourque, G, Gerstein, M, Park, PJ, Wedge, DC, Beroukhim, R, Torrents, D, Korbel, JO, Martincorena, I, Fitzgerald, RC, Van Loo, P, Kazazian, HH, Burns, KH, Akdemir, KC, Alvarez, EG, Baez-Ortega, A, Beroukhim, R, Boutros, PC, Bowtell, DDL, Brors, B, Burns, KH, Campbell, PJ, Chan, K, Chen, K, Cortés-Ciriano, I, Dueso-Barroso, A, Dunford, AJ, Edwards, PA, Estivill, X, Etemadmoghadam, D, Feuerbach, L, Fink, JL, Frenkel-Morgenstern, M, Garsed, DW, Gerstein, M, Gordenin, DA, Haan, D, Haber, JE, Hess, JM, Hutter, B, Imielinski, M, Jones, DTW, Ju, YS, Kazanov, MD, Klimczak, LJ, Koh, Y, Korbel, JO, Kumar, K, Lee, EA, Lee, JJ-K, Li, Y, Lynch, AG, Macintyre, G, Markowetz, F, Martincorena, I, Martinez-Fundichely, A, Meyerson, M, Miyano, S, Nakagawa, H, Navarro, FCP, Ossowski, S, Park, PJ, Pearson, JV, Puiggròs, M, Rippe, K, Roberts, ND, Roberts, SA, Rodriguez-Martin, B, Schumacher, SE, Scully, R, Shackleton, M, Sidiropoulos, N, Sieverling, L, Stewart, C, Torrents, D, Tubio, JMC, Villasante, I, Waddell, N, Wala, JA, Weischenfeldt, J, Yang, L, Yao, X, Yoon, S-S, Zamora, J, Zhang, C-Z, Campbell, PJ & Tubio, JMC 2020, 'Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition', Nature Genetics, vol. 52, no. 3, pp. 306-319. https://doi.org/10.1038/s41588-019-0562-0

TY - JOUR

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

AU - Rodriguez-Martin, B.

AU - Alvarez, E.G.

AU - Baez-Ortega, A.

AU - Zamora, J.

AU - Supek, F.

AU - Demeulemeester, J.

AU - Santamarina, M.

AU - Ju, Y.S.

AU - Temes, J.

AU - Garcia-Souto, D.

AU - Detering, H.

AU - Li, Y.

AU - Rodriguez-Castro, J.

AU - Dueso-Barroso, A.

AU - Bruzos, A.L.

AU - Dentro, S.C.

AU - Blanco, M.G.

AU - Contino, G.

AU - Ardeljan, D.

AU - Tojo, M.

AU - Roberts, N.D.

AU - Zumalave, S.

AU - Edwards, P.A.

AU - Weischenfeldt, J.

AU - Puiggròs, M.

AU - Chong, Z.

AU - Chen, K.

AU - Lee, E.A.

AU - Wala, J.A.

AU - Raine, K.

AU - Butler, A.

AU - Waszak, S.M.

AU - Navarro, F.C.P.

AU - Schumacher, S.E.

AU - Monlong, J.

AU - Maura, F.

AU - Bolli, N.

AU - Bourque, G.

AU - Gerstein, M.

AU - Park, P.J.

AU - Wedge, D.C.

AU - Beroukhim, R.

AU - Torrents, D.

AU - Korbel, J.O.

AU - Martincorena, I.

AU - Fitzgerald, R.C.

AU - Van Loo, P.

AU - Kazazian, H.H.

AU - Burns, K.H.

AU - Akdemir, K.C.

AU - Alvarez, E.G.

AU - Baez-Ortega, A.

AU - Beroukhim, R.

AU - Boutros, P.C.

AU - Bowtell, D.D.L.

AU - Brors, B.

AU - Burns, K.H.

AU - Campbell, P.J.

AU - Chan, K.

AU - Chen, K.

AU - Cortés-Ciriano, I.

AU - Dueso-Barroso, A.

AU - Dunford, A.J.

AU - Edwards, P.A.

AU - Estivill, X.

AU - Etemadmoghadam, D.

AU - Feuerbach, L.

AU - Fink, J.L.

AU - Frenkel-Morgenstern, M.

AU - Garsed, D.W.

AU - Gerstein, M.

AU - Gordenin, D.A.

AU - Haan, D.

AU - Haber, J.E.

AU - Hess, J.M.

AU - Hutter, B.

AU - Imielinski, M.

AU - Jones, D.T.W.

AU - Ju, Y.S.

AU - Kazanov, M.D.

AU - Klimczak, L.J.

AU - Koh, Y.

AU - Korbel, J.O.

AU - Kumar, K.

AU - Lee, E.A.

AU - Lee, J.J.-K.

AU - Li, Y.

AU - Lynch, A.G.

AU - Macintyre, G.

AU - Markowetz, F.

AU - Martincorena, I.

AU - Martinez-Fundichely, A.

AU - Meyerson, M.

AU - Miyano, S.

AU - Nakagawa, H.

AU - Navarro, F.C.P.

AU - Ossowski, S.

AU - Park, P.J.

AU - Pearson, J.V.

AU - Puiggròs, M.

AU - Rippe, K.

AU - Roberts, N.D.

AU - Roberts, S.A.

AU - Rodriguez-Martin, B.

AU - Schumacher, S.E.

AU - Scully, R.

AU - Shackleton, M.

AU - Sidiropoulos, N.

AU - Sieverling, L.

AU - Stewart, C.

AU - Torrents, D.

AU - Tubio, J.M.C.

AU - Villasante, I.

AU - Waddell, N.

AU - Wala, J.A.

AU - Weischenfeldt, J.

AU - Yang, L.

AU - Yao, X.

AU - Yoon, S.-S.

AU - Zamora, J.

AU - Zhang, C.-Z.

AU - Campbell, P.J.

AU - Tubio, J.M.C.

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.

KW - Carcinogenesis/genetics

KW - Gene Rearrangement/genetics

KW - Genome, Human/genetics

KW - Humans

KW - Long Interspersed Nucleotide Elements/genetics

KW - Neoplasms/genetics

KW - Retroelements/genetics

U2 - 10.1038/s41588-019-0562-0

DO - 10.1038/s41588-019-0562-0

M3 - Article

C2 - 32024998

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

Keywords

Research Beacons, Institutes and Platforms

UN SDGs

Access to Document

Fingerprint

Cite this