A practical framework and online tool for mutational signature analyses show intertissue variation and driver dependencies
Top Cited Papers
- 14 February 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Cancer
- Vol. 1 (2), 249-263
- https://doi.org/10.1038/s43018-020-0027-5
Abstract
Mutational signatures are patterns of mutations that arise during tumorigenesis. We present an enhanced, practical framework for mutational signature analyses. Applying these methods to 3,107 whole-genome-sequenced (WGS) primary cancers of 21 organs reveals known signatures and nine previously undescribed rearrangement signatures. We highlight interorgan variability of signatures and present a way of visualizing that diversity, reinforcing our findings in an independent analysis of 3,096 WGS metastatic cancers. Signatures with a high level of genomic instability are dependent on TP53 dysregulation. We illustrate how uncertainty in mutational signature identification and assignment to samples affects tumor classification, reinforcing that using multiple orthogonal mutational signature data is not only beneficial, but is also essential for accurate tumor stratification. Finally, we present a reference web-based tool for cancer and experimentally generated mutational signatures, called Signal (https://signal.mutationalsignatures.com), that also supports performing mutational signature analyses.Keywords
Funding Information
- Cancer Research UK (C60100/A23433, C60100/A23433, C60100/A23916, C60100/A25274)
- Wellcome Trust (WT100126/B/13/Z)
This publication has 32 references indexed in Scilit:
- Portrait of a cancer: mutational signature analyses for cancer diagnosticsBMC Cancer, 2019
- Computational approaches for discovery of mutational signatures in cancerBriefings in Bioinformatics, 2017
- Pan-cancer analysis of whole genomesPublished by Cold Spring Harbor Laboratory ,2017
- HRDetect is a predictor of BRCA1 and BRCA2 deficiency based on mutational signaturesNature Medicine, 2017
- Somatic ERCC2 mutations are associated with a distinct genomic signature in urothelial tumorsNature Genetics, 2016
- Deciphering Signatures of Mutational Processes Operative in Human CancerCell Reports, 2013
- Mutational Processes Molding the Genomes of 21 Breast CancersCell, 2012
- Patterns of somatic mutation in human cancer genomesNature, 2007
- Nonsmooth nonnegative matrix factorization (nsNMF)Ieee Transactions On Pattern Analysis and Machine Intelligence, 2006
- Learning the parts of objects by non-negative matrix factorizationNature, 1999