Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Stefan C. Dentro; Ignaty Leshchiner; Kerstin Haase; Maxime Tarabichi; Jeff Wintersinger; Amit G. Deshwar; Kaixian Yu; Yulia Rubanova; Geoff Macintyre; Jonas Demeulemeester; Ignacio Vázquez-García; Kortine Kleinheinz; Dimitri G. Livitz; Salem Malikic; Nilgun Donmez; Subhajit Sengupta; Pavana Anur; Clemency Jolly; Marek Cmero; Daniel Rosebrock; Steven E. Schumacher; Yu Fan; Matthew Fittall; Ruben M. Drews; Xiaotong Yao; Thomas B.K. Watkins; Juhee Lee; Matthias Schlesner; Hongtu Zhu; David J. Adams; Nicholas McGranahan; Charles Swanton; Gad Getz; Paul C. Boutros; Marcin Imielinski; Rameen Beroukhim; S. Cenk Sahinalp; Yuan Ji; Martin Peifer; Inigo Martincorena; Florian Markowetz; Ville Mustonen; Ke Yuan; Moritz Gerstung; Paul T. Spellman; Wenyi Wang; Quaid D. Morris; David C. Wedge; Peter Van Loo; Santiago Gonzalez; David D. Bowtell; Peter J. Campbell; Shaolong Cao; Elizabeth L. Christie; Yupeng Cun; Kevin J. Dawson; Roland Eils; Dale W. Garsed; Gavin Ha; Lara Jerman; Henry Lee-Six; Thomas J. Mitchell; Layla Oesper; Myron Peto; Benjamin J. Raphael; Adriana Salcedo; Ruian Shi; Seung Jun Shin; Lincoln D. Stein; Oliver Spiro; Shankar Vembu; David A. Wheeler; Tsun Po Yang

doi:10.1016/j.cell.2021.03.009

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

Stefan C. Dentro, Ignaty Leshchiner, Kerstin Haase, Maxime Tarabichi, Jeff Wintersinger, Amit G. Deshwar, Kaixian Yu, Yulia Rubanova, Geoff Macintyre, Jonas Demeulemeester, Ignacio Vázquez-García, Kortine Kleinheinz, Dimitri G. Livitz, Salem Malikic, Nilgun Donmez, Subhajit Sengupta, Pavana Anur, Clemency Jolly, Marek Cmero, Daniel RosebrockSteven E. Schumacher, Yu Fan, Matthew Fittall, Ruben M. Drews, Xiaotong Yao, Thomas B.K. Watkins, Juhee Lee, Matthias Schlesner, Hongtu Zhu, David J. Adams, Nicholas McGranahan, Charles Swanton, Gad Getz, Paul C. Boutros, Marcin Imielinski, Rameen Beroukhim, S. Cenk Sahinalp, Yuan Ji, Martin Peifer, Inigo Martincorena, Florian Markowetz, Ville Mustonen, Ke Yuan, Moritz Gerstung, Paul T. Spellman, Wenyi Wang, Quaid D. Morris, David C. Wedge, Peter Van Loo, Santiago Gonzalez, David D. Bowtell, Peter J. Campbell, Shaolong Cao, Elizabeth L. Christie, Yupeng Cun, Kevin J. Dawson, Roland Eils, Dale W. Garsed, Gavin Ha, Lara Jerman, Henry Lee-Six, Thomas J. Mitchell, Layla Oesper, Myron Peto, Benjamin J. Raphael, Adriana Salcedo, Ruian Shi, Seung Jun Shin, Lincoln D. Stein, Oliver Spiro, Shankar Vembu, David A. Wheeler, Tsun Po Yang

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

120 Scopus citations

Abstract

Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

Original language	English (US)
Pages (from-to)	2239-2254.e39
Journal	Cell
Volume	184
Issue number	8
DOIs	https://doi.org/10.1016/j.cell.2021.03.009
State	Published - Apr 15 2021

All Science Journal Classification (ASJC) codes

Biochemistry, Genetics and Molecular Biology(all)

Keywords

branching evolution
cancer driver genes
cancer evolution
intra-tumor heterogeneity
pan-cancer genomics
subclonal reconstruction
tumor phylogeny
whole-genome sequencing

Access to Document

10.1016/j.cell.2021.03.009

Cite this

Dentro, S. C., Leshchiner, I., Haase, K., Tarabichi, M., Wintersinger, J., Deshwar, A. G., Yu, K., Rubanova, Y., Macintyre, G., Demeulemeester, J., Vázquez-García, I., Kleinheinz, K., Livitz, D. G., Malikic, S., Donmez, N., Sengupta, S., Anur, P., Jolly, C., Cmero, M., ... Yang, T. P. (2021). Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes. Cell, 184(8), 2239-2254.e39. https://doi.org/10.1016/j.cell.2021.03.009

@article{dd547ac9226a4fe9b44423a973289416,

title = "Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes",

abstract = "Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.",

keywords = "branching evolution, cancer driver genes, cancer evolution, intra-tumor heterogeneity, pan-cancer genomics, subclonal reconstruction, tumor phylogeny, whole-genome sequencing",

author = "Dentro, {Stefan C.} and Ignaty Leshchiner and Kerstin Haase and Maxime Tarabichi and Jeff Wintersinger and Deshwar, {Amit G.} and Kaixian Yu and Yulia Rubanova and Geoff Macintyre and Jonas Demeulemeester and Ignacio V{\'a}zquez-Garc{\'i}a and Kortine Kleinheinz and Livitz, {Dimitri G.} and Salem Malikic and Nilgun Donmez and Subhajit Sengupta and Pavana Anur and Clemency Jolly and Marek Cmero and Daniel Rosebrock and Schumacher, {Steven E.} and Yu Fan and Matthew Fittall and Drews, {Ruben M.} and Xiaotong Yao and Watkins, {Thomas B.K.} and Juhee Lee and Matthias Schlesner and Hongtu Zhu and Adams, {David J.} and Nicholas McGranahan and Charles Swanton and Gad Getz and Boutros, {Paul C.} and Marcin Imielinski and Rameen Beroukhim and Sahinalp, {S. Cenk} and Yuan Ji and Martin Peifer and Inigo Martincorena and Florian Markowetz and Ville Mustonen and Ke Yuan and Moritz Gerstung and Spellman, {Paul T.} and Wenyi Wang and Morris, {Quaid D.} and Wedge, {David C.} and {Van Loo}, Peter and Santiago Gonzalez and Bowtell, {David D.} and Campbell, {Peter J.} and Shaolong Cao and Christie, {Elizabeth L.} and Yupeng Cun and Dawson, {Kevin J.} and Roland Eils and Garsed, {Dale W.} and Gavin Ha and Lara Jerman and Henry Lee-Six and Mitchell, {Thomas J.} and Layla Oesper and Myron Peto and Raphael, {Benjamin J.} and Adriana Salcedo and Ruian Shi and Shin, {Seung Jun} and Stein, {Lincoln D.} and Oliver Spiro and Shankar Vembu and Wheeler, {David A.} and Yang, {Tsun Po}",

note = "Funding Information: This work was 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 ). This project was enabled through the Crick Scientific Computing STP and through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council ( MR/L016311/1 ). M.T. and J.D. are postdoctoral fellows supported by the European Union Horizon 2020 Research and Innovation Program (Marie Sk{\l}odowska-Curie grant agreements 747852-SIOMICS and 703594-DECODE ). J.D. is a postdoctoral fellow of the Research Foundation – Flanders (FWO). I.V.G. is supported by a Wellcome Trust PhD fellowship ( WT097678 ) and the Ann and Sol Schreiber Mentored Investigator Award of the Ovarian Cancer Research Alliance . S.M. is funded by a Vanier Canada graduate scholarship. S.C.S. is supported by the NSERC Discovery Frontiers Project “The Cancer Genome Collaboratory” and by NIH GM108308 . D.J.A. is supported by Cancer Research UK . F.M., G.M., and K. Yuan acknowledge support from the University of Cambridge , Cancer Research UK , and Hutchison Whampoa Limited . G.M., K. Yuan, and F.M. are funded by CRUK core grants C14303/A17197 and A19274 . K. Yuan is further supported by EPSRC EP/R018634/1 . S.S. and Y.J. are supported by NIH R01 CA132897 . H.Z. is supported by grant NIMH086633 and an endowed Bao-Shan Jing Professorship in Diagnostic Imaging. P.T.S. is supported by U24CA210957 and 1U24CA143799 . N.M. is a Sir Henry Dale Fellow, funded jointly by the Wellcome Trust and the Royal Society ( 211179/Z/18/Z ) and also receives funding from Cancer Research UK , Rosetrees and the NIHR BRC at University College London Hospitals , and the CRUK University College London Experimental Cancer Medicine Centre . T.B.K.W. and C.S. are supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( FC001169 ), the UK Medical Research Council ( FC001169 ), and the Wellcome Trust ( FC001169 ). C.S. is Royal Society Napier Research Professor ( RP150154 ). T.B.K.W. receives support from a Royal Society Research Professorships Enhancement Award ( RP/EA/180007 ). W.W. is supported by the National Cancer Institute ( 1R01 CA183793 and P30 CA016672 ). D.C.W. is funded by the Li Ka Shing Foundation . P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation {\textquoteright}s support toward establishment of The Francis Crick Institute. We acknowledge the contributions of the many clinical networks across 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 participation in the individual ICGC and TCGA projects. Funding Information: This work was 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). This project was enabled through the Crick Scientific Computing STP and through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (MR/L016311/1). M.T. and J.D. are postdoctoral fellows supported by the European Union Horizon 2020 Research and Innovation Program (Marie Sk?odowska-Curie grant agreements 747852-SIOMICS and 703594-DECODE). J.D. is a postdoctoral fellow of the Research Foundation ? Flanders (FWO). I.V.G. is supported by a Wellcome Trust PhD fellowship (WT097678) and the Ann and Sol Schreiber Mentored Investigator Award of the Ovarian Cancer Research Alliance. S.M. is funded by a Vanier Canada graduate scholarship. S.C.S. is supported by the NSERC Discovery Frontiers Project ?The Cancer Genome Collaboratory? and by NIH GM108308. D.J.A. is supported by Cancer Research UK. F.M. G.M. and K. Yuan acknowledge support from the University of Cambridge, Cancer Research UK, and Hutchison Whampoa Limited. G.M. K. Yuan, and F.M. are funded by CRUK core grants C14303/A17197 and A19274. K. Yuan is further supported by EPSRC EP/R018634/1. S.S. and Y.J. are supported by NIH R01 CA132897. H.Z. is supported by grant NIMH086633 and an endowed Bao-Shan Jing Professorship in Diagnostic Imaging. P.T.S. is supported by U24CA210957 and 1U24CA143799. N.M. is a Sir Henry Dale Fellow, funded jointly by the Wellcome Trust and the Royal Society (211179/Z/18/Z) and also receives funding from Cancer Research UK, Rosetrees and the NIHR BRC at University College London Hospitals, and the CRUK University College London Experimental Cancer Medicine Centre. T.B.K.W. and C.S. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is Royal Society Napier Research Professor (RP150154). T.B.K.W. receives support from a Royal Society Research Professorships Enhancement Award (RP/EA/180007). W.W. is supported by the National Cancer Institute (1R01 CA183793 and P30 CA016672). D.C.W. is funded by the Li Ka Shing Foundation. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support toward establishment of The Francis Crick Institute. We acknowledge the contributions of the many clinical networks across 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 participation in the individual ICGC and TCGA projects. S.C.D. I.L. J.W. A.G.D. I.V.-G. K. Yuan, G.M. M.P. S.M. N.D. K. Yu, S.S. K.H. M.T. J.D. D.G.L. G.G. D.R. J.L. M.C. S.C.S. Y.J. F.M. V.M. H.Z. W.W. Q.D.M. D.C.W. and P.V.L. performed subclonal architecture analyses. S.C.D. I.L. A.G.D. K. Yuan, S.M. N.D. M.P. S.S. I.V.-G. K.H. G.M. V.M. F.M. Q.D.M. D.C.W. and P.V.L. calibrated subclonal architecture methods. S.C.D. I.L. K.K. V.M. I.V.-G. M.P. X.Y. D.G.L. S.E.S. R.B. M.I. M.S. D.C.W. and P.V.L. performed copy number analyses. J.W. S.C.D. I.L. K.H. D.G.L. K.K. D.R. D.C.W. Q.D.M. and P.V.L. derived a consensus of copy number analysis results. K. Yu, M.T. A.G.D. S.C.D. D.C.W. M.G. P.V.L. Q.D.M. and W.W. derived a consensus of subclonal architecture results. M.T. S.C.D. I.L. D.R. D.G.L. Q.D.M. W.W. M.G. D.C.W. G.G. and P.V.L. performed simulations. K. Yu, M.T. A.G.D. Q.D.M. P.V.L. and W.W. performed scoring. Y.F. and W.W. contributed to subclonal mutation calls. S.C.D. I.L. K.H. A.G.D. P.A. C.J. M.F. D.J.A. P.C.B. M.G. W.W. Q.D.M. D.C.W. and P.V.L. performed exploratory analyses. I.L. A.G.D. D.G.L. K.H. G.G. Q.D.M. and P.V.L. performed power analyses. S.C.D. Y.R. Q.D.M. and P.V.L. performed mutational signature analyses. I.L. K.H. S.C.D. M.T. G.G. I.M. and P.V.L. performed SNV and indel driver analyses. G.M. R.M.D. and F.M. performed SV driver analyses. I.L. D.R. and G.G. performed fusion clonality analyses. J.D. A.G.D. S.C.D. I.L. M.T. Q.D.M. and P.V.L. performed mutation phasing analyses. J.D. T.B.K.W. N.M. C.S. and P.V.L. performed TRACERx analyses. P.T.S. W.W. Q.D.M. D.C.W. and P.V.L. coordinated the study. S.C.D. I.L. K.H. Y.R. M.T. G.M. J.D. R.M.D. P.T.S. W.W. Q.D.M. D.C.W. and P.V.L. wrote the manuscript with input from all authors. All authors approved the final version of the manuscript. G.M. and F.M. are cofounders and shareholders of Tailor Bio. R.B. owns equity in Ampressa Therapeutics. G.G. receives research funds from IBM and Pharmacyclics and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect, and POLYSOLVER. I.L. is a consultant for PACT Pharma. B.J.R. is a consultant at and has ownership interest (including stock and patents) in Medley Genomics. N.M. has stock options in and has consulted for Achilles Therapeutics. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx, and Ono Pharmaceutical; is an AstraZeneca Advisory Board Member and Chief Investigator for the MeRmaiD-1 clinical trial; has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Celgene, AstraZeneca, Illumina, Amgen, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute; has stock options in Apogen Biotechnologies, Epic Bioscience, and GRAIL; and has stock options and is co-founder of Achilles Therapeutics. Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = apr,

day = "15",

doi = "10.1016/j.cell.2021.03.009",

language = "English (US)",

volume = "184",

pages = "2239--2254.e39",

journal = "Cell",

issn = "0092-8674",

publisher = "Cell Press",

number = "8",

}

Dentro, SC, Leshchiner, I, Haase, K, Tarabichi, M, Wintersinger, J, Deshwar, AG, Yu, K, Rubanova, Y, Macintyre, G, Demeulemeester, J, Vázquez-García, I, Kleinheinz, K, Livitz, DG, Malikic, S, Donmez, N, Sengupta, S, Anur, P, Jolly, C, Cmero, M, Rosebrock, D, Schumacher, SE, Fan, Y, Fittall, M, Drews, RM, Yao, X, Watkins, TBK, Lee, J, Schlesner, M, Zhu, H, Adams, DJ, McGranahan, N, Swanton, C, Getz, G, Boutros, PC, Imielinski, M, Beroukhim, R, Sahinalp, SC, Ji, Y, Peifer, M, Martincorena, I, Markowetz, F, Mustonen, V, Yuan, K, Gerstung, M, Spellman, PT, Wang, W, Morris, QD, Wedge, DC, Van Loo, P, Gonzalez, S, Bowtell, DD, Campbell, PJ, Cao, S, Christie, EL, Cun, Y, Dawson, KJ, Eils, R, Garsed, DW, Ha, G, Jerman, L, Lee-Six, H, Mitchell, TJ, Oesper, L, Peto, M, Raphael, BJ, Salcedo, A, Shi, R, Shin, SJ, Stein, LD, Spiro, O, Vembu, S, Wheeler, DA & Yang, TP 2021, 'Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes', Cell, vol. 184, no. 8, pp. 2239-2254.e39. https://doi.org/10.1016/j.cell.2021.03.009

TY - JOUR

T1 - Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

AU - Dentro, Stefan C.

AU - Leshchiner, Ignaty

AU - Haase, Kerstin

AU - Tarabichi, Maxime

AU - Wintersinger, Jeff

AU - Deshwar, Amit G.

AU - Yu, Kaixian

AU - Rubanova, Yulia

AU - Macintyre, Geoff

AU - Demeulemeester, Jonas

AU - Vázquez-García, Ignacio

AU - Kleinheinz, Kortine

AU - Livitz, Dimitri G.

AU - Malikic, Salem

AU - Donmez, Nilgun

AU - Sengupta, Subhajit

AU - Anur, Pavana

AU - Jolly, Clemency

AU - Cmero, Marek

AU - Rosebrock, Daniel

AU - Schumacher, Steven E.

AU - Fan, Yu

AU - Fittall, Matthew

AU - Drews, Ruben M.

AU - Yao, Xiaotong

AU - Watkins, Thomas B.K.

AU - Lee, Juhee

AU - Schlesner, Matthias

AU - Zhu, Hongtu

AU - Adams, David J.

AU - McGranahan, Nicholas

AU - Swanton, Charles

AU - Getz, Gad

AU - Boutros, Paul C.

AU - Imielinski, Marcin

AU - Beroukhim, Rameen

AU - Sahinalp, S. Cenk

AU - Ji, Yuan

AU - Peifer, Martin

AU - Martincorena, Inigo

AU - Markowetz, Florian

AU - Mustonen, Ville

AU - Yuan, Ke

AU - Gerstung, Moritz

AU - Spellman, Paul T.

AU - Wang, Wenyi

AU - Morris, Quaid D.

AU - Wedge, David C.

AU - Van Loo, Peter

AU - Gonzalez, Santiago

AU - Bowtell, David D.

AU - Campbell, Peter J.

AU - Cao, Shaolong

AU - Christie, Elizabeth L.

AU - Cun, Yupeng

AU - Dawson, Kevin J.

AU - Eils, Roland

AU - Garsed, Dale W.

AU - Ha, Gavin

AU - Jerman, Lara

AU - Lee-Six, Henry

AU - Mitchell, Thomas J.

AU - Oesper, Layla

AU - Peto, Myron

AU - Raphael, Benjamin J.

AU - Salcedo, Adriana

AU - Shi, Ruian

AU - Shin, Seung Jun

AU - Stein, Lincoln D.

AU - Spiro, Oliver

AU - Vembu, Shankar

AU - Wheeler, David A.

AU - Yang, Tsun Po

N1 - Funding Information: This work was 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 ). This project was enabled through the Crick Scientific Computing STP and through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council ( MR/L016311/1 ). M.T. and J.D. are postdoctoral fellows supported by the European Union Horizon 2020 Research and Innovation Program (Marie Skłodowska-Curie grant agreements 747852-SIOMICS and 703594-DECODE ). J.D. is a postdoctoral fellow of the Research Foundation – Flanders (FWO). I.V.G. is supported by a Wellcome Trust PhD fellowship ( WT097678 ) and the Ann and Sol Schreiber Mentored Investigator Award of the Ovarian Cancer Research Alliance . S.M. is funded by a Vanier Canada graduate scholarship. S.C.S. is supported by the NSERC Discovery Frontiers Project “The Cancer Genome Collaboratory” and by NIH GM108308 . D.J.A. is supported by Cancer Research UK . F.M., G.M., and K. Yuan acknowledge support from the University of Cambridge , Cancer Research UK , and Hutchison Whampoa Limited . G.M., K. Yuan, and F.M. are funded by CRUK core grants C14303/A17197 and A19274 . K. Yuan is further supported by EPSRC EP/R018634/1 . S.S. and Y.J. are supported by NIH R01 CA132897 . H.Z. is supported by grant NIMH086633 and an endowed Bao-Shan Jing Professorship in Diagnostic Imaging. P.T.S. is supported by U24CA210957 and 1U24CA143799 . N.M. is a Sir Henry Dale Fellow, funded jointly by the Wellcome Trust and the Royal Society ( 211179/Z/18/Z ) and also receives funding from Cancer Research UK , Rosetrees and the NIHR BRC at University College London Hospitals , and the CRUK University College London Experimental Cancer Medicine Centre . T.B.K.W. and C.S. are supported by the Francis Crick Institute , which receives its core funding from Cancer Research UK ( FC001169 ), the UK Medical Research Council ( FC001169 ), and the Wellcome Trust ( FC001169 ). C.S. is Royal Society Napier Research Professor ( RP150154 ). T.B.K.W. receives support from a Royal Society Research Professorships Enhancement Award ( RP/EA/180007 ). W.W. is supported by the National Cancer Institute ( 1R01 CA183793 and P30 CA016672 ). D.C.W. is funded by the Li Ka Shing Foundation . P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation ’s support toward establishment of The Francis Crick Institute. We acknowledge the contributions of the many clinical networks across 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 participation in the individual ICGC and TCGA projects. Funding Information: This work was 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). This project was enabled through the Crick Scientific Computing STP and through access to the MRC eMedLab Medical Bioinformatics infrastructure, supported by the Medical Research Council (MR/L016311/1). M.T. and J.D. are postdoctoral fellows supported by the European Union Horizon 2020 Research and Innovation Program (Marie Sk?odowska-Curie grant agreements 747852-SIOMICS and 703594-DECODE). J.D. is a postdoctoral fellow of the Research Foundation ? Flanders (FWO). I.V.G. is supported by a Wellcome Trust PhD fellowship (WT097678) and the Ann and Sol Schreiber Mentored Investigator Award of the Ovarian Cancer Research Alliance. S.M. is funded by a Vanier Canada graduate scholarship. S.C.S. is supported by the NSERC Discovery Frontiers Project ?The Cancer Genome Collaboratory? and by NIH GM108308. D.J.A. is supported by Cancer Research UK. F.M. G.M. and K. Yuan acknowledge support from the University of Cambridge, Cancer Research UK, and Hutchison Whampoa Limited. G.M. K. Yuan, and F.M. are funded by CRUK core grants C14303/A17197 and A19274. K. Yuan is further supported by EPSRC EP/R018634/1. S.S. and Y.J. are supported by NIH R01 CA132897. H.Z. is supported by grant NIMH086633 and an endowed Bao-Shan Jing Professorship in Diagnostic Imaging. P.T.S. is supported by U24CA210957 and 1U24CA143799. N.M. is a Sir Henry Dale Fellow, funded jointly by the Wellcome Trust and the Royal Society (211179/Z/18/Z) and also receives funding from Cancer Research UK, Rosetrees and the NIHR BRC at University College London Hospitals, and the CRUK University College London Experimental Cancer Medicine Centre. T.B.K.W. and C.S. are supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC001169), the UK Medical Research Council (FC001169), and the Wellcome Trust (FC001169). C.S. is Royal Society Napier Research Professor (RP150154). T.B.K.W. receives support from a Royal Society Research Professorships Enhancement Award (RP/EA/180007). W.W. is supported by the National Cancer Institute (1R01 CA183793 and P30 CA016672). D.C.W. is funded by the Li Ka Shing Foundation. P.V.L. is a Winton Group Leader in recognition of the Winton Charitable Foundation's support toward establishment of The Francis Crick Institute. We acknowledge the contributions of the many clinical networks across 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 participation in the individual ICGC and TCGA projects. S.C.D. I.L. J.W. A.G.D. I.V.-G. K. Yuan, G.M. M.P. S.M. N.D. K. Yu, S.S. K.H. M.T. J.D. D.G.L. G.G. D.R. J.L. M.C. S.C.S. Y.J. F.M. V.M. H.Z. W.W. Q.D.M. D.C.W. and P.V.L. performed subclonal architecture analyses. S.C.D. I.L. A.G.D. K. Yuan, S.M. N.D. M.P. S.S. I.V.-G. K.H. G.M. V.M. F.M. Q.D.M. D.C.W. and P.V.L. calibrated subclonal architecture methods. S.C.D. I.L. K.K. V.M. I.V.-G. M.P. X.Y. D.G.L. S.E.S. R.B. M.I. M.S. D.C.W. and P.V.L. performed copy number analyses. J.W. S.C.D. I.L. K.H. D.G.L. K.K. D.R. D.C.W. Q.D.M. and P.V.L. derived a consensus of copy number analysis results. K. Yu, M.T. A.G.D. S.C.D. D.C.W. M.G. P.V.L. Q.D.M. and W.W. derived a consensus of subclonal architecture results. M.T. S.C.D. I.L. D.R. D.G.L. Q.D.M. W.W. M.G. D.C.W. G.G. and P.V.L. performed simulations. K. Yu, M.T. A.G.D. Q.D.M. P.V.L. and W.W. performed scoring. Y.F. and W.W. contributed to subclonal mutation calls. S.C.D. I.L. K.H. A.G.D. P.A. C.J. M.F. D.J.A. P.C.B. M.G. W.W. Q.D.M. D.C.W. and P.V.L. performed exploratory analyses. I.L. A.G.D. D.G.L. K.H. G.G. Q.D.M. and P.V.L. performed power analyses. S.C.D. Y.R. Q.D.M. and P.V.L. performed mutational signature analyses. I.L. K.H. S.C.D. M.T. G.G. I.M. and P.V.L. performed SNV and indel driver analyses. G.M. R.M.D. and F.M. performed SV driver analyses. I.L. D.R. and G.G. performed fusion clonality analyses. J.D. A.G.D. S.C.D. I.L. M.T. Q.D.M. and P.V.L. performed mutation phasing analyses. J.D. T.B.K.W. N.M. C.S. and P.V.L. performed TRACERx analyses. P.T.S. W.W. Q.D.M. D.C.W. and P.V.L. coordinated the study. S.C.D. I.L. K.H. Y.R. M.T. G.M. J.D. R.M.D. P.T.S. W.W. Q.D.M. D.C.W. and P.V.L. wrote the manuscript with input from all authors. All authors approved the final version of the manuscript. G.M. and F.M. are cofounders and shareholders of Tailor Bio. R.B. owns equity in Ampressa Therapeutics. G.G. receives research funds from IBM and Pharmacyclics and is an inventor on patent applications related to MuTect, ABSOLUTE, MutSig, MSMuTect, and POLYSOLVER. I.L. is a consultant for PACT Pharma. B.J.R. is a consultant at and has ownership interest (including stock and patents) in Medley Genomics. N.M. has stock options in and has consulted for Achilles Therapeutics. C.S. acknowledges grant support from Pfizer, AstraZeneca, Bristol Myers Squibb, Roche-Ventana, Boehringer-Ingelheim, Archer Dx, and Ono Pharmaceutical; is an AstraZeneca Advisory Board Member and Chief Investigator for the MeRmaiD-1 clinical trial; has consulted for Pfizer, Novartis, GlaxoSmithKline, MSD, Bristol Myers Squibb, Celgene, AstraZeneca, Illumina, Amgen, Genentech, Roche-Ventana, GRAIL, Medicxi, Bicycle Therapeutics, and the Sarah Cannon Research Institute; has stock options in Apogen Biotechnologies, Epic Bioscience, and GRAIL; and has stock options and is co-founder of Achilles Therapeutics. Publisher Copyright: © 2021 The Author(s)

PY - 2021/4/15

Y1 - 2021/4/15

N2 - Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

AB - Intra-tumor heterogeneity (ITH) is a mechanism of therapeutic resistance and therefore an important clinical challenge. However, the extent, origin, and drivers of ITH across cancer types are poorly understood. To address this, we extensively characterize ITH across whole-genome sequences of 2,658 cancer samples spanning 38 cancer types. Nearly all informative samples (95.1%) contain evidence of distinct subclonal expansions with frequent branching relationships between subclones. We observe positive selection of subclonal driver mutations across most cancer types and identify cancer type-specific subclonal patterns of driver gene mutations, fusions, structural variants, and copy number alterations as well as dynamic changes in mutational processes between subclonal expansions. Our results underline the importance of ITH and its drivers in tumor evolution and provide a pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.

KW - branching evolution

KW - cancer driver genes

KW - cancer evolution

KW - intra-tumor heterogeneity

KW - pan-cancer genomics

KW - subclonal reconstruction

KW - tumor phylogeny

KW - whole-genome sequencing

UR - http://www.scopus.com/inward/record.url?scp=85103719722&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85103719722&partnerID=8YFLogxK

U2 - 10.1016/j.cell.2021.03.009

DO - 10.1016/j.cell.2021.03.009

M3 - Article

C2 - 33831375

AN - SCOPUS:85103719722

SN - 0092-8674

VL - 184

SP - 2239-2254.e39

JO - Cell

JF - Cell

IS - 8

ER -

Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes

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