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Reconstructing evolutionary trajectories of mutation signature activities in cancer using TrackSig.

Published version
Peer-reviewed

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Authors

Rubanova, Yulia 
Shi, Ruian 
Harrigan, Caitlin F  ORCID logo  https://orcid.org/0000-0002-9243-9648
Li, Roujia 
Wintersinger, Jeff 

Abstract

The type and genomic context of cancer mutations depend on their causes. These causes have been characterized using signatures that represent mutation types that co-occur in the same tumours. However, it remains unclear how mutation processes change during cancer evolution due to the lack of reliable methods to reconstruct evolutionary trajectories of mutational signature activity. Here, as part of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium, which aggregated whole-genome sequencing data from 2658 cancers across 38 tumour types, we present TrackSig, a new method that reconstructs these trajectories using optimal, joint segmentation and deconvolution of mutation type and allele frequencies from a single tumour sample. In simulations, we find TrackSig has a 3-5% activity reconstruction error, and 12% false detection rate. It outperforms an aggressive baseline in situations with branching evolution, CNA gain, and neutral mutations. Applied to data from 2658 tumours and 38 cancer types, TrackSig permits pan-cancer insight into evolutionary changes in mutational processes.

Description

Keywords

Computational Biology, Computer Simulation, Evolution, Molecular, Gene Frequency, Genome, Human, Humans, Mutation, Neoplasms, Polymorphism, Single Nucleotide, Whole Genome Sequencing

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

11

Publisher

Springer Science and Business Media LLC