Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes
SUMMARY 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 question, 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 an unprecedented pan-cancer resource of comprehensively annotated subclonal events from whole-genome sequencing data.
Schlesner Matthias、Wintersinger Jeff、Leshchiner Ignaty、Deshwar Amit G.、Malikic Salem、Jolly Clemency、Lee Juhee、Adams David J.、Imielinski Marcin、Beroukhim Rameen、Van Loo Peter、on behalf of the PCAWG Evolution and Heterogeneity Working Groupthe PCAWG consortium.、Zhu Hongtu、Wedge David C.、Rubanova Yulia、Tarabichi Maxime、Drews Ruben M.、Fittall Matthew、Yu Kaixian、Haase Kerstin、Yao Xiaotong、Mustonen Ville、Getz Gad、Markowetz Florian、Spellman Paul T.、Sahinalp S. Cenk、V¨￠zquez-Garc¨aa Ignacio、Demeulemeester Jonas、Anur Pavana、Dentro Stefan C.、Sengupta Subhajit、the PCAWG consortium、Cmero Marek、Rosebrock Daniel、Schumacher Steven、Kleinheinz Kortine、Boutros Paul C.、Ji Yuan、Fan Yu、Donmez Nilgun、Livitz Dimitri G.、Martincorena Inigo、Macintyre Geoff、Wang Wenyi、Peifer Martin、Gerstung Moritz、Morris Quaid D.、Yuan Ke
Computational OncologyUniversity of TorontoBroad Institute of MIT and HarvardUniversity of TorontoSimon Fraser UniversityThe Francis Crick InstituteUniversity of California Santa CruzWellcome Trust Sanger InstituteWeill Cornell Medicine||New York Genome CenterBroad Institute of MIT and HarvardThe Francis Crick InstituteThe University of Texas MD Anderson Cancer CenterBig Data Institute, University of Oxford||Oxford NIHR Biomedical Research CentreUniversity of TorontoThe Francis Crick Institute||Wellcome Trust Sanger InstituteCancer Research UK Cambridge Institute, University of CambridgeThe Francis Crick InstituteThe University of Texas MD Anderson Cancer CenterThe Francis Crick InstituteWeill Cornell Medicine||New York Genome CenterOrganismal and Evolutionary Biology Research Programme, Department of Computer Science, Institute of Biotechnology, University of HelsinkiBroad Institute of MIT and HarvardCancer Research UK Cambridge Institute, University of CambridgeMolecular and Medical Genetics, Oregon Health & Science UniversityIndiana UniversityWellcome Trust Sanger Institute||University of Cambridge||Computational Oncology||Irving Institute for Cancer Dynamics, Columbia UniversityThe Francis Crick Institute||Department of Human Genetics, University of LeuvenMolecular and Medical Genetics, Oregon Health & Science UniversityThe Francis Crick Institute||Wellcome Trust Sanger Institute||Big Data Institute, University of OxfordNorthShore University HealthSystemUniversity of MelbourneBroad Institute of MIT and HarvardBroad Institute of MIT and HarvardGerman Cancer Research Center (DKFZ)||Heidelberg UniversityUniversity of Toronto||University of CaliforniaNorthShore University HealthSystem||The University of ChicagoThe University of Texas MD Anderson Cancer CenterSimon Fraser UniversityBroad Institute of MIT and HarvardWellcome Trust Sanger InstituteCancer Research UK Cambridge Institute, University of CambridgeThe University of Texas MD Anderson Cancer CenterUniversity of CologneEuropean Molecular Biology Laboratory, European Bioinformatics InstituteUniversity of TorontoCancer Research UK Cambridge Institute, University of Cambridge||School of Computing Science, University of Glasgow
肿瘤学遗传学生物科学研究方法、生物科学研究技术
Schlesner Matthias,Wintersinger Jeff,Leshchiner Ignaty,Deshwar Amit G.,Malikic Salem,Jolly Clemency,Lee Juhee,Adams David J.,Imielinski Marcin,Beroukhim Rameen,Van Loo Peter,on behalf of the PCAWG Evolution and Heterogeneity Working Groupthe PCAWG consortium.,Zhu Hongtu,Wedge David C.,Rubanova Yulia,Tarabichi Maxime,Drews Ruben M.,Fittall Matthew,Yu Kaixian,Haase Kerstin,Yao Xiaotong,Mustonen Ville,Getz Gad,Markowetz Florian,Spellman Paul T.,Sahinalp S. Cenk,V¨￠zquez-Garc¨aa Ignacio,Demeulemeester Jonas,Anur Pavana,Dentro Stefan C.,Sengupta Subhajit,the PCAWG consortium,Cmero Marek,Rosebrock Daniel,Schumacher Steven,Kleinheinz Kortine,Boutros Paul C.,Ji Yuan,Fan Yu,Donmez Nilgun,Livitz Dimitri G.,Martincorena Inigo,Macintyre Geoff,Wang Wenyi,Peifer Martin,Gerstung Moritz,Morris Quaid D.,Yuan Ke.Characterizing genetic intra-tumor heterogeneity across 2,658 human cancer genomes[EB/OL].(2025-03-28)[2025-05-05].https://www.biorxiv.org/content/10.1101/312041.点此复制
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