Abstract
Germline polymorphisms and somatic alterations drive parallel evolution of metastasis.
Major finding: Germline polymorphisms and somatic alterations drive parallel evolution of metastasis.
Approach: WES was performed on a genetically heterogeneous mouse model of mutagen-induced squamous carcinomas.
Impact: Mouse models reflecting the heterogeneity of human cancers provide insight into metastatic evolution.
Advances in next-generation sequencing have enabled the genomic characterization of human cancers. However, due to the lack of appropriately matched primary tumors and metastases, the genetic determinants driving the evolution of metastasis have not been identified. To analyze the clonal evolution of metastatic carcinomas, McCreery and colleagues analyzed a genetically heterogeneous mouse population which, after sequential treatment with the carcinogens dimethylbenzanthracene (DMBA) and 12-O-tetradecanoylphorbol-13-acetate (TPA), formed tumors recapitulating all stages of human squamous tumors, in particular squamous cell carcinomas harboring Hras or Kras mutations. Whole-exome sequencing (WES) and gene expression analysis of 103 matched benign, malignant, and metastatic tumors from mice treated with DMBA and TPA showed that A-to-T mutations, which are associated with DMBA, were shared, early clonal events, while G-to-T mutations, which are associated with TPA and oxidative stress, were later nonshared, subclonal events. Moreover, tumors exhibited allelic preference for Hras and Kras mutations. Phylogenetic analysis of the mutation spectra exhibited by the tumors in each mouse showed that metastatic dissemination occurred independently and in parallel and may be dependent on tumor-intrinsic factors. In most cases, metastases morphologically matched the primary tumors in all target organs except for some lung metastases, which had undergone mesenchymal-to-epithelial transition (MET), indicating that MET may be organ-specific. Analysis of the WES data revealed that copy-number variants (CNV) were specifically related to a particular initiating Ras mutation and that early papillomas, representing the earliest stage of carcinoma, exhibited a mutation spectrum similar to that of more advanced tumors but harbored only a single CNV, suggesting that most single-nucleotide variants were acquired prior to CNVs. Together, these findings show that the sequence of mutations that occurs in a genetically heterogeneous mouse model of skin tumors induced by specific initiating mutagens permits detailed clonal analysis of the evolution of metastasis and may identify therapeutic targets.
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