Integrated clinicogenomic analysis reveals the evolution and metastatic tropisms of advanced colorectal cancer.
We performed an integrated clinical and genomic analysis of over 7,000 consecutively sequenced colorectal cancer (CRC) samples to comprehensively characterize genetic drivers and metastatic tropisms of CRC. We find that genomic evolutionary changes, such as clonal mutations and oncogenic mutant allelic imbalance, selectively enhance the impact of recurrent oncogenic alterations. We identify the relative timing of organ-specific metastasis, showing sequential metastatic progression in microsatellite stable CRC with brain and adrenal metastases as late events; metastatic sites that cluster together, such as lung, bone, and brain metastases; and genomic events that enhance or decrease risk for each metastatic site, with WNT pathway activation as overall protective while RAS pathway activation increased risk for spread to all metastatic sites. Our data suggest that despite the heterogeneity in CRC, genomic evolution increases the impact of recurrent alterations, and integrating information about tumor primary location and genomics can be used to predict organ-specific metastasis risk.