Evolution of metastasis revealed by mutational landscapes of chemically induced skin cancers

Abstract

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.

Metabolic Plasticity as a Determinant of Tumor Growth and Metastasis

“…In accordance with this model, recent genomic studies of matched primary tumors and metastases suggest independent evolution (76,77). Interestingly, the study of chemically induced skin tumors and metastases suggest that common mutations have an A-to-T signature indicative of the carcinogen while nonshared mutations are G-to-T transitions that signify exposure to oxidative stress (76). Accumulating evidence suggests that disseminating cancer cells undergo profound metabolic reprogramming during the discrete steps to successfully metastasize.…”

“…In contrast, an alternate hypothesis, referred to as the "parallel progression model," has been proposed that argues metastatic dissemination is an early event during tumor progression (74,75). In accordance with this model, recent genomic studies of matched primary tumors and metastases suggest independent evolution (76,77). Interestingly, the study of chemically induced skin tumors and metastases suggest that common mutations have an A-to-T signature indicative of the carcinogen while nonshared mutations are G-to-T transitions that signify exposure to oxidative stress (76).…”

The Role of Aneuploidy in Cancer Evolution

“…This relieves the selective pressure to maintain the initial genetic lesion, and is therefore not subject to oncogene addiction. Mouse models of skin and pancreatic cancers have similarly shown that CIN drives metastatic progression (Hingorani et al 2005;McCreery et al 2015). In human tumors, increase in CIN has been linked to metastatic progression in prostate cancer, pancreatic cancer, breast cancer, colorectal cancer, and renal cell carcinoma (reviewed in Turajlic and Swanton 2016).…”

Genome Evolution Analysis of Recurrent Testicular Malignant Mesothelioma by Whole-Genome Sequencing

“…Progression of cancer can be depicted under the hypothesis of tumor evolution models. However, although the branched evolution model has been widely accepted, it is under debate regarding the metastatic routes of cancer cells [3]. Both linear and parallel models are supported by evidence.…”