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 | |
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
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In: Cell, Vol. 184, No. 8, 15.04.2021, p. 2239-2254.e39.
Research output: Contribution to journal › Article › peer-review
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 -