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

被引：293

作者：

Dentro, Stefan C. ^{[1
,2
,3
]}

Leshchiner, Ignaty ^{[4
]}

Haase, Kerstin ^{[1
]}

Tarabichi, Maxime ^{[1
,2
]}

Wintersinger, Jeff ^{[5
,6
]}

Deshwar, Amit G. ^{[5
,6
]}

Yu, Kaixian ^{[7
]}

Rubanova, Yulia ^{[5
,6
]}

Macintyre, Geoff ^{[8
]}

Demeulemeester, Jonas ^{[1
,9
]}

Vazquez-Garcia, Ignacio ^{[2
,10
,11
,12
]}

Kleinheinz, Kortine ^{[13
,14
]}

Livitz, Dimitri G. ^{[4
]}

Malikic, Salem ^{[15
]}

Donmez, Nilgun ^{[16
,17
]}

Sengupta, Subhajit ^{[18
]}

Anur, Pavana ^{[19
]}

Jolly, Clemency ^{[1
]}

Cmero, Marek ^{[20
,21
]}

Rosebrock, Daniel ^{[4
]}

Schumacher, Steven E. ^{[4
]}

Fan, Yu ^{[7
]}

Fittall, Matthew ^{[1
]}

Drews, Ruben M. ^{[8
]}

Yao, Xiaotong ^{[22
,23
]}

Watkins, Thomas B. K. ^{[24
]}

Lee, Juhee ^{[25
]}

Schlesner, Matthias ^{[13
]}

Zhu, Hongtu ^{[7
]}

Adams, David J. ^{[2
]}

McGranahan, Nicholas ^{[26
,27
]}

Swanton, Charles ^{[24
,26
,28
]}

Getz, Gad ^{[4
,29
,30
,31
]}

Boutros, Paul C. ^{[5
,32
,33
]}

Imielinski, Marcin ^{[22
,23
]}

Beroukhim, Rameen ^{[4
,34
]}

Sahinalp, S. Cenk ^{[15
]}

Ji, Yuan ^{[18
,35
]}

Peifer, Martin ^{[36
]}

Martincorena, Inigo ^{[2
]}

Markowetz, Florian ^{[8
]}

Mustonen, Ville ^{[37
]}

Yuan, Ke ^{[8
,38
]}

Gerstung, Moritz ^{[2
,39
,40
]}

Spellman, Paul T. ^{[19
,41
]}

Wang, Wenyi ^{[7
]}

Morris, Quaid D. ^{[5
,6
,32
]}

Wedge, David C. ^{[3
,42
,43
]}

Van Loo, Peter ^{[1
]}

机构：

[1] Francis Crick Inst, Canc Genom Lab, London NW1 1AT, England

[2] Wellcome Trust Sanger Inst, Cambridge CB10 1SA, England

[3] Univ Oxford, Big Data Inst, Cambridge OX3 7LF, England

[4] Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] Univ Toronto, Toronto, ON M5S 3E1, Canada

[6] Vector Inst, Toronto, ON M5G 1L7, Canada

[7] Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA

[8] Univ Cambridge, Canc Res UK Cambridge Inst, Cambridge CB2 0RE, England

[9] Univ Leuven, Dept Human Genet, B-3000 Leuven, Belgium

[10] Univ Cambridge, Cambridge CB2 0QQ, England

[11] Mem Sloan Kettering Canc Ctr, Computat Oncol, New York, NY 10065 USA

[12] Columbia Univ, Irving Inst Canc Dynam, New York, NY 10027 USA

[13] German Canc Res Ctr, D-69120 Heidelberg, Germany

[14] Heidelberg Univ, D-69120 Heidelberg, Germany

[15] NIH, Canc Data Sci Lab, NCI, Bethesda, MD 20892 USA

[16] Simon Fraser Univ, Burnaby, BC V5A 1S6, Canada

[17] Vancouver Prostate Ctr, Vancouver, BC V6H 3Z6, Canada

[18] NorthShore Univ HealthSyst, Evanston, IL 60201 USA

[19] Oregon Hlth & Sci Univ, Mol & Med Genet, Portland, OR 97231 USA

[20] Univ Melbourne, Melbourne, Vic 3010, Australia

[21] Walter Eliza Hall Inst, Melbourne, Vic 3000, Australia

[22] Weill Cornell Med, New York, NY 10065 USA

[23] New York Genome Ctr, New York, NY 10013 USA

[24] Francis Crick Inst, Canc Evolut & Genome Instabil Lab, London NW1 1AT, England

[25] Univ Calif Santa Cruz, Santa Cruz, CA 95064 USA

[26] Univ Coll London Canc Inst, Canc Res UK Lung Canc Ctr Excellence, London WC1E 6BT, England

[27] UCL, Canc Inst, Canc Genome Evolut Res Grp, London WC1E 6DD, England

[28] Univ Coll London Hosp, Dept Med Oncol, London NW1 2BU, England

[29] Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA

[30] Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA

[31] Harvard Med Sch, Boston, MA 02215 USA

[32] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada

[33] Univ Calif Los Angeles, Los Angeles, CA 90095 USA

[34] Dana Farber Canc Inst, Boston, MA 02215 USA

[35] Univ Chicago, Chicago, IL 60637 USA

[36] Univ Cologne, Med Fac, Ctr Integrated Oncol Cologne Bonn, Dept Translat Genom, D-50931 Cologne, Germany

[37] Univ Helsinki, Inst Biotechnol, Dept Comp Sci, Organismal & Evolutionary Biol Res Programme, Helsinki 00014, Finland

[38] Univ Glasgow, Sch Comp Sci, Glasgow G12 8RZ, Lanark, Scotland

[39] European Bioinformat Inst EMBL EBI, European Mol Biol Lab, Cambridge CB10 1SD, England

[40] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany

[41] Mem Sloan Kettering Canc Ctr, Computat & Syst Biol, New York, NY 10065 USA

[42] Oxford NIHR Biomed Res Ctr, Oxford OX4 2PG, England

[43] Univ Manchester, Manchester Canc Res Ctr, Manchester M20 4GJ, Lancs, England

来源：

CELL | 2021年 / 184卷 / 08期

基金：

英国工程与自然科学研究理事会; 加拿大自然科学与工程研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

COPY-NUMBER ANALYSIS; MUTATIONAL SIGNATURES; PREDICTS PROGRESSION; EVOLUTIONARY HISTORY; VARIABLE SELECTION; DENSITY-ESTIMATION; SOMATIC MUTATIONS; CLONAL EVOLUTION; RB1; GENE; INFERENCE;

D O I：

10.1016/j.cell.2021.03.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2239 / +

页数：55

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