Somatic mutation distribution across tumour cohorts provides a signal for positive selection in cancer

Martin Boström and Erik Larsson ()
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Martin Boström: University of Gothenburg
Erik Larsson: University of Gothenburg

Nature Communications, 2022, vol. 13, issue 1, 1-9

Abstract: Abstract Cancer gene discovery is reliant on distinguishing driver mutations from a multitude of passenger mutations in tumour genomes. While driver genes may be revealed based on excess mutation recurrence or clustering, there is a need for orthogonal principles. Here, we take advantage of the fact that non-cancer genes, containing only passenger mutations under neutral selection, exhibit a likelihood of mutagenesis in a given tumour determined by the tumour’s mutational signature and burden. This relationship can be disrupted by positive selection, leading to a difference in the distribution of mutated cases across a cohort for driver and passenger genes. We apply this principle to detect cancer drivers independently of recurrence in large pan-cancer cohorts, and show that our method (SEISMIC) performs comparably to traditional approaches and can provide resistance to known confounding mutational phenomena. Being based on a different principle, the approach provides a much-needed complement to existing methods for detecting signals of selection.

Date: 2022
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DOI: 10.1038/s41467-022-34746-z

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