Quantitative evidence for early metastatic seeding in colorectal cancer

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 colorectal cancer (CRC) patients with metastases to the liver or brain. The data show low primary tumor-metastasis genomic divergence, where canonical driver genes were acquired early. Analysis within a spatial tumor growth model and statistical inference framework indicates that early disseminated cells commonly (81%, 17/21 evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically <0.01 cm(3)). We validated the association between early drivers and metastasis in an independent cohort of 2,751 CRCs, demonstrating their utility as biomarkers of metastasis. This new conceptual and analytical framework provides quantitative in vivo evidence that systemic spread can occur early in CRC and illuminates strategies for patient stratification and therapeutic targeting of the canonical drivers of tumorigenesis.