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Bayesian inference of negative and positive selection in human cancers

Nature Genetics volume 49, pages 1785–1788 (2017)Cite this article

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Abstract

Cancer genomics efforts have identified genes and regulatory elements driving cancer development and neoplastic progression. From a microevolution standpoint, these are subject to positive selection. Although elusive in current studies, genes whose wild-type coding sequences are needed for tumor growth are also of key interest. They are expected to experience negative selection and stay intact under pressure of incessant mutation. The detection of significantly mutated (or undermutated) genes is completely confounded by the genomic heterogeneity of cancer mutation1. Here we present a hierarchical framework that allows modeling of coding point mutations. Application of the model to sequencing data from 17 cancer types demonstrates an increased power to detect known cancer driver genes and identifies new significantly mutated genes with highly plausible biological functions. The signal of negative selection is very subtle, but is detectable in several cancer types and in a pan-cancer data set. It is enriched in cell-essential genes identified in a CRISPR screen2, as well as in genes with reported roles in cancer.

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Figure 1: Observed and expected neutral distributions of mutation counts per gene.
Figure 2: Per-gene inference of selection and validation.
Figure 3: Genome-wide intensity of selection.

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Acknowledgements

We thank S. Schiffels and L. Mirny for helpful discussion during the conception of the project and feedback on the manuscript, as well as P. Polak and Z. Li for critical reading of the manuscript. We also thank V. Seplyarskiy for advice on mutational processes and I. Adzhubey for support with the setup of the web interface for CBaSE. This work was supported by US National Institutes of Health (NIH) grants U54 CA143874, R01 MH101244, and R01 GM078598 (S.S.).

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Authors and Affiliations

  1. Department of Medicine, Division of Genetics, Brigham and Women's Hospital/Harvard Medical School, Boston, Massachusetts, USA

    Donate Weghorn & Shamil Sunyaev

  2. Department of Biomedical Informatics, Harvard Medical School, Boston, Massachusetts, USA

    Donate Weghorn & Shamil Sunyaev

Authors
  1. Donate Weghorn
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  2. Shamil Sunyaev
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Contributions

D.W. designed the statistical framework, wrote code, analyzed and interpreted data, created the web interface, and wrote the manuscript. S.S. supervised the project, gave technical and conceptual advice, and wrote the manuscript.

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Correspondence to Shamil Sunyaev.

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The authors declare no competing financial interests.

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Weghorn, D., Sunyaev, S. Bayesian inference of negative and positive selection in human cancers. Nat Genet 49, 1785–1788 (2017). https://doi.org/10.1038/ng.3987

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