Passenger Mutations in More Than 2,500 Cancer Genomes: Overall Molecular Functional Impact and Consequences.

DNA Mutational Analysis / methods Disease Progression Genome, Human / genetics Genomics / methods Humans Mutation / genetics Neoplasms / genetics Whole Genome Sequencing
PCAWG additive-efects cancer genomics deleterious passengers driver mutations molecular impact passenger mutations weak drivers

Journal

Cell
ISSN: 1097-4172
Titre abrégé: Cell
Pays: United States
ID NLM: 0413066

Informations de publication

Date de publication:
05 03 2020
Historique:
received: 01 10 2018
revised: 23 08 2019
accepted: 29 01 2020
pubmed: 23 2 2020
medline: 18 8 2020
entrez: 22 2 2020
Statut: ppublish

Résumé

The dichotomous model of "drivers" and "passengers" in cancer posits that only a few mutations in a tumor strongly affect its progression, with the remaining ones being inconsequential. Here, we leveraged the comprehensive variant dataset from the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) project to demonstrate that-in addition to the dichotomy of high- and low-impact variants-there is a third group of medium-impact putative passengers. Moreover, we also found that molecular impact correlates with subclonal architecture (i.e., early versus late mutations), and different signatures encode for mutations with divergent impact. Furthermore, we adapted an additive-effects model from complex-trait studies to show that the aggregated effect of putative passengers, including undetected weak drivers, provides significant additional power (∼12% additive variance) for predicting cancerous phenotypes, beyond PCAWG-identified driver mutations. Finally, this framework allowed us to estimate the frequency of potential weak-driver mutations in PCAWG samples lacking any well-characterized driver alterations.

Identifiants

DOI: 10.1016/j.cell.2020.01.032 PMID: 32084333 PMC: PMC7210002
pubmed: 32084333
pii: S0092-8674(20)30113-6
doi: 10.1016/j.cell.2020.01.032
pmc: PMC7210002
mid: NIHMS1568958
pii:
doi:

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

915-927.e16

Subventions

Organisme : NCI NIH HHS
ID : R01 CA218668
Pays : United States
Organisme : NHGRI NIH HHS
ID : R01 HG008126
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007205
Pays : United States

Informations de copyright

Copyright © 2020 Elsevier Inc. All rights reserved.

Déclaration de conflit d'intérêts

Declaration of Interests G.G. received funds from IBM and Pharmacyclics. G.G. is listed as inventor for multiple patent applications including MuTect, ABSOLUTE, POLYSOLVER, MutSig, and MSMuTect.

Références

Nat Rev Cancer. 2004 Mar;4(3):177-83
pubmed: 14993899
Nat Rev Genet. 2016 Feb;17(2):93-108
pubmed: 26781813
Nature. 2014 Jan 23;505(7484):495-501
pubmed: 24390350
Nature. 2012 Sep 6;489(7414):57-74
pubmed: 22955616
Science. 2013 Oct 04;342(6154):1235587
pubmed: 24092746
Nucleic Acids Res. 2014 Mar;42(5):2976-87
pubmed: 24335146
Nat Rev Genet. 2014 Sep;15(9):585-98
pubmed: 24981601
Nature. 2013 Jul 11;499(7457):214-218
pubmed: 23770567
Am J Hum Genet. 2011 Mar 11;88(3):294-305
pubmed: 21376301
Genome Biol. 2020 Nov 9;21(1):274
pubmed: 33168059
Nature. 2015 Oct 1;526(7571):75-81
pubmed: 26432246
Nat Rev Cancer. 2015 Nov;15(11):680-5
pubmed: 26456849
N Engl J Med. 2015 Nov 12;373(20):1895-8
pubmed: 26559569
Nucleic Acids Res. 2006 Jan 1;34(Database issue):D158-62
pubmed: 16381836
Methods Mol Biol. 2006;342:129-38
pubmed: 16957372
Science. 2013 Mar 29;339(6127):1546-58
pubmed: 23539594
Cell. 2018 Apr 5;173(2):305-320.e10
pubmed: 29625049
Science. 2015 Nov 27;350(6264):1096-101
pubmed: 26472758
Genome Res. 2010 Apr;20(4):447-57
pubmed: 20103589
Nucleic Acids Res. 2011 Jan;39(Database issue):D691-7
pubmed: 21067998
Nucleic Acids Res. 2003 Jan 1;31(1):439-41
pubmed: 12520045
Oral Oncol. 2013 Mar;49(3):211-5
pubmed: 23079694
Nature. 2016 Aug 17;536(7616):285-91
pubmed: 27535533
BMC Med Genomics. 2019 May 20;12(1):64
pubmed: 31109337
Nat Genet. 2013 Oct;45(10):1127-33
pubmed: 24071851
BMC Bioinformatics. 2014 Feb 01;15:35
pubmed: 24484323
Nature. 2015 Feb 19;518(7539):317-30
pubmed: 25693563
Am J Hum Genet. 2011 Jan 7;88(1):76-82
pubmed: 21167468
Nucleic Acids Res. 2016 Jan 4;44(D1):D110-5
pubmed: 26531826
Nat Commun. 2017 Aug 29;8(1):382
pubmed: 28851873
Genome Res. 2005 Jul;15(7):901-13
pubmed: 15965027
Genome Res. 2012 Sep;22(9):1760-74
pubmed: 22955987
Genome Biol. 2014;15(10):480
pubmed: 25273974
Trends Genet. 2013 Mar;29(3):150-9
pubmed: 23219555
Nature. 2009 Aug 6;460(7256):748-52
pubmed: 19571811
Nucleic Acids Res. 1996 Jan 1;24(1):238-41
pubmed: 8594589
Nat Genet. 2015 Jul;47(7):710-6
pubmed: 26053494
Nature. 2015 Oct 1;526(7571):68-74
pubmed: 26432245
Proc Natl Acad Sci U S A. 2013 Feb 19;110(8):2910-5
pubmed: 23388632
Nat Genet. 2013 Oct;45(10):1113-20
pubmed: 24071849
Nature. 2013 Aug 22;500(7463):415-21
pubmed: 23945592
Nature. 2017 Jul 6;547(7661):55-60
pubmed: 28658208
Nat Rev Mol Cell Biol. 2008 Dec;9(12):958-70
pubmed: 19023283
Nucleic Acids Res. 2016 Jul 8;44(W1):W54-7
pubmed: 27174935
Nature. 2017 Jul 6;547(7661):40-41
pubmed: 28658210
Nat Genet. 2015 Mar;47(3):199-208
pubmed: 25599403
Bioinformatics. 2010 Mar 15;26(6):841-2
pubmed: 20110278
Nat Genet. 2010 Jul;42(7):565-9
pubmed: 20562875
Genome Res. 2010 Jan;20(1):110-21
pubmed: 19858363
Nucleic Acids Res. 2013 Jan;41(Database issue):D56-63
pubmed: 23193274

Auteurs

Sushant Kumar (S)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.

Jonathan Warrell (J)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.

Shantao Li (S)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.

Patrick D McGillivray (PD)

Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Yale School of Medicine, Yale University, New Haven, CT 06510, USA.

William Meyerson (W)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Yale School of Medicine, Yale University, New Haven, CT 06510, USA.

Leonidas Salichos (L)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.

Arif Harmanci (A)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Center for Precision Health, School of Biomedical Informatics, University of Texas Health Sciences Center, Houston, TX 77030, USA.

Alexander Martinez-Fundichely (A)

Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.

Calvin W Y Chan (CWY)

Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg 69120, Germany.

Morten Muhlig Nielsen (MM)

Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark.

Lucas Lochovsky (L)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.

Yan Zhang (Y)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Biomedical Informatics, College of Medicine, Ohio State University, Columbus, OH 43210, USA; The Ohio State University Comprehensive Cancer Center (OSUCCC-James), Columbus, OH 43210, USA.

Xiaotong Li (X)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.

Shaoke Lou (S)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA.

Jakob Skou Pedersen (JS)

Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark; Bioinformatics Research Centre (BiRC), Aarhus University, Aarhus, Denmark.

Carl Herrmann (C)

Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Health Data Science Unit, Medical Faculty Heidelberg and BioQuant, Heidelberg 69120, Germany.

Gad Getz (G)

The Broad Institute of MIT and Harvard, Cambridge, MA 02124, USA; Massachusetts General Hospital Center for Cancer Research, Charlestown, MA 02129, USA; Harvard Medical School, 250 Longwood Avenue, Boston, MA 02115, USA.

Ekta Khurana (E)

Institute for Computational Biomedicine, Weill Cornell Medical College, New York, NY 10021, USA; Department of Physiology and Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, NY 10065, USA; Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA; Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.

Mark B Gerstein (MB)

Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Department of Computer Science, Yale University, New Haven, CT 06511, USA. Electronic address: mark@gersteinlab.org.

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Analyse de mutations d'ADN › Passenger Mutations in More Than 2,500 Cancer...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Caractéristiques de la maladie › Évolution de la maladie › Passenger Mutations in More Than 2,500 Cancer...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Génome humain › Passenger Mutations in More Than 2,500 Cancer...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Passenger Mutations in More Than 2,500 Cancer...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Passenger Mutations in More Than 2,500 Cancer...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Passenger Mutations in More Than 2,500 Cancer...
questionsmedicales.fr › Tumeurs › Passenger Mutations in More Than 2,500 Cancer...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Passenger Mutations in More Than 2,500 Cancer...