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

Sushant Kumar; Jonathan Warrell; Shantao Li; Patrick D McGillivray; William Meyerson; Leonidas Salichos; Arif Harmanci; Alexander Martinez-Fundichely; Calvin W Y Chan; Morten Muhlig Nielsen; Lucas Lochovsky; Yan Zhang; Xiaotong Li; Shaoke Lou; Jakob Skou Pedersen; Carl Herrmann; Gad Getz; Ekta Khurana; Mark B Gerstein

doi:10.1016/j.cell.2020.01.032

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

Cell. 2020 Mar 5;180(5):915-927.e16. doi: 10.1016/j.cell.2020.01.032. Epub 2020 Feb 20.

Authors

Sushant Kumar¹, Jonathan Warrell¹, Shantao Li¹, Patrick D McGillivray², William Meyerson³, Leonidas Salichos¹, Arif Harmanci⁴, Alexander Martinez-Fundichely⁵, Calvin W Y Chan⁶, Morten Muhlig Nielsen⁷, Lucas Lochovsky¹, Yan Zhang⁸, Xiaotong Li⁹, Shaoke Lou¹, Jakob Skou Pedersen¹⁰, Carl Herrmann¹¹, Gad Getz¹², Ekta Khurana¹³, Mark B Gerstein¹⁴

Affiliations

¹ 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.
² Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520, USA; Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
³ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA; Yale School of Medicine, Yale University, New Haven, CT 06510, USA.
⁴ 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.
⁵ 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.
⁶ Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Faculty of Biosciences, Heidelberg University, Heidelberg 69120, Germany.
⁷ Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark.
⁸ 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.
⁹ Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT 06520, USA.
¹⁰ Department of Molecular Medicine (MOMA), Aarhus University Hospital, Aarhus, Denmark; Bioinformatics Research Centre (BiRC), Aarhus University, Aarhus, Denmark.
¹¹ Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Health Data Science Unit, Medical Faculty Heidelberg and BioQuant, Heidelberg 69120, Germany.
¹² 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.
¹³ 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.
¹⁴ 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.

Abstract

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.

Keywords: PCAWG; additive-efects; cancer genomics; deleterious passengers; driver mutations; molecular impact; passenger mutations; weak drivers.

Publication types

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

MeSH terms

DNA Mutational Analysis / methods
Disease Progression
Genome, Human / genetics*
Genomics / methods*
Humans
Mutation / genetics*
Neoplasms / genetics*
Neoplasms / pathology
Whole Genome Sequencing

Abstract

Publication types

MeSH terms

Grants and funding