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Sci Rep. 2017 Aug 9;7(1):7645. doi: 10.1038/s41598-017-07888-0.

A pooled mutational analysis identifies ionizing radiation-associated mutational signatures conserved between mouse and human malignancies.

Author information

1
Department of Finance and Statistical Analysis, University of Alberta, Edmonton, Alberta, T6G 2R3, Canada.
2
Department of Radiation Oncology, University of California, San Francisco, California, 94158, USA.
3
Memorial Sloan Kettering Cancer Center, New York, 10065, USA.
4
Department of Radiation Oncology, University of California, San Francisco, California, 94158, USA. Jean.Nakamura@ucsf.edu.

Abstract

Single nucleotide variants (SNVs) identified in cancer genomes can be de-convolved using non-negative matrix factorization (NMF) into discrete trinucleotide-based mutational signatures indicative of specific cancer-causing processes. The stability of NMF-generated mutational signatures depends upon the numbers of variants available for analysis. In this work, we sought to assess whether data from well-controlled mouse models can compensate for scarce human data for some cancer types. High quality sequencing data from radiotherapy-induced cancers is particularly scarce and the mutational processes defining ionizing radiation (IR)-induced mutagenesis in vivo are poorly defined. Here, we combine sequencing data from mouse models of IR-induced malignancies and human IR-induced malignancies. To determine whether the signatures identified from IR-exposed subjects can be differentiated from other mutagenic signatures, we included data from an ultraviolet radiation (UV)-induced human skin cancer and from a mouse model of urethane-induced cancers. NMF distinguished all three mutagens and in the pooled analysis IR was associated with mutational signatures common to both species. These findings illustrate the utility of pooled analysis of mouse and human sequencing data.

PMID:
28794481
PMCID:
PMC5550450
DOI:
10.1038/s41598-017-07888-0
[Indexed for MEDLINE]
Free PMC Article

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