Journal article

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 Vazquez-Garcia, Kortine Kleinheinz, Dimitri G Livitz, Salem Malikic, Nilgun Donmez, Subhajit Sengupta, Pavana Anur, Clemency Jolly, Marek Cmero, Daniel Rosebrock Show all

CELL | CELL PRESS | Published : 2021

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 alte..

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Grants

Awarded by Cancer Research UK


Awarded by UK Medical Research Council


Awarded by Wellcome Trust


Awarded by Medical Research Council


Awarded by European Union


Awarded by Wellcome Trust PhD fellowship


Awarded by CRUK


Awarded by EPSRC


Awarded by NIH


Awarded by Royal Society


Awarded by Royal Society Research Professorships Enhancement Award


Awarded by National Cancer Institute



Funding Acknowledgements

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 Sk1odowska-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.