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

223 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

Keywords

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

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

MD Anderson CCSG core facilities

Biostatistics Resource Group
Bioinformatics Shared Resource

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10.1016/j.cell.2021.03.009

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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

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

@article{84490f8812ae4442b1521938e34e019c,

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 = "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",

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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

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

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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

Abstract

Keywords

ASJC Scopus subject areas

MD Anderson CCSG core facilities

Access to Document

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