Quantitative evidence for early metastatic seeding in colorectal cancer

• Published in: Nature genetics Vol. 51; no. 7; pp. 1113 - 1122
• Main Authors: Hu, Zheng, Ding, Jie, Ma, Zhicheng, Sun, Ruping, Seoane, Jose A., Scott Shaffer, J., Suarez, Carlos J., Berghoff, Anna S., Cremolini, Chiara, Falcone, Alfredo, Loupakis, Fotios, Birner, Peter, Preusser, Matthias, Lenz, Heinz-Josef, Curtis, Christina
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2019; Nature Publishing Group
• Subjects: 631/208/212; 631/67; 692/699/67/1504/1885; Agriculture; Animal Genetics and Genomics; Bioinformatics; Biomarkers; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Brain; Brain Neoplasms - genetics; Brain Neoplasms - secondary; Cancer; Cancer Research; Case-Control Studies; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Deoxyribonucleic acid; Divergence; DNA; DNA Copy Number Variations; DNA methylation; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Gene Function; Genomes; Genomics - methods; Human Genetics; Humans; Liver; Liver Neoplasms - genetics; Liver Neoplasms - secondary; Mathematical models; Metastases; Metastasis; Mutation; Patients; Phylogenetics; Retrospective Studies; Spatial analysis; Statistical inference; Therapeutic targets; Tumorigenesis; Tumors; United States > US
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/s41588-019-0423-x

Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts. Here we characterize the evolutionary dynamics of this lethal process by analyzing exome-sequencing data from 118 biopsies from 23 patients with colorectal cancer with metastases to the liver or brain. The data show that the genomic divergence between the primary tumor and metastasis is low and that canonical driver genes were acquired early. Analysis within a spatial tumor growth model and statistical inference framework indicates that early disseminated cells commonly (81%, 17 out of 21 evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically, less than 0.01 cm 3 ). We validated the association between early drivers and metastasis in an independent cohort of 2,751 colorectal cancers, demonstrating their utility as biomarkers of metastasis. This conceptual and analytical framework provides quantitative in vivo evidence that systemic spread can occur early in colorectal cancer and illuminates strategies for patient stratification and therapeutic targeting of the canonical drivers of tumorigenesis. Analysis of evolutionary dynamics of colorectal cancers and paired distant brain or liver metastases provides evidence that early disseminated cancer cells seed metastases before the carcinoma is clinically detectable.