Human tumors show a high level of genetic heterogeneity, but the processes that influence the timing and route of metastatic dissemination of the subclones are unknown. Here we have used whole-exome sequencing of 103 matched benign, malignant and metastatic skin tumors from genetically heterogeneous mice to demonstrate that most metastases disseminate synchronously from the primary tumor, supporting parallel rather than linear evolution as the predominant model of metastasis. Shared mutations between primary carcinomas and their matched metastases have the distinct A-to-T signature of the initiating carcinogen dimethylbenzanthracene, but non-shared mutations are primarily G-to-T, a signature associated with oxidative stress. The existence of carcinomas that either did or did not metastasize in the same host animal suggests that there are tumor-intrinsic factors that influence metastatic seeding. We also demonstrate the importance of germline polymorphisms in determining allele-specific mutations, and we identify somatic genetic alterations that are specifically related to initiation of carcinogenesis by Hras or Kras mutations. Mouse tumors that mimic the genetic heterogeneity of human cancers can aid our understanding of the clonal evolution of metastasis and provide a realistic model for the testing of novel therapies.
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This work was supported by US National Cancer Institute (NCI) grants UO1 CA84244 (A.B.), UO1 CA141455 (A.B.), UO1 CA176287 (A.B.) and RO1CA184510 (A.B.), and the Barbara Bass Bakar Distinguished Professorship in Cancer Genetics. K.D.H. was supported by the US National Institutes of Health training grant T32 GM007175 and is currently supported by an NCI F31 National Research Service Award (NRSA). D.J.A. is supported by Cancer Research UK and the Wellcome Trust. We thank our colleagues for their help and comments in refining this study and manuscript. We would also like to thank R. Kettleborough and R. White (both at the Wellcome Trust Sanger Institute) for assistance with MiSeq analysis and E. Wu, K. Copren and the UCSF Helen Diller Family Comprehensive Cancer Cancer Center Genome Analysis Core for assistance with Affymetrix microarrays and with sequencing.
The authors declare no competing financial interests.
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McCreery, M., Halliwill, K., Chin, D. et al. Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers. Nat Med 21, 1514–1520 (2015). https://doi.org/10.1038/nm.3979
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