Negative Selection Maintains Grossly Altered but Broadly Stable Karyotypes in Metastatic Colorectal Cancer.
Cross WCH., Nowinski S., Cresswell GD., Mossner M., Banerjee A., Lu B., Williams MJ., Vlachogiannis G., Gay LJ., Baker A-M., Kimberley C., Whiting FJH., Belnoue-Davis HL., Martinez P., Traki M., Walther V., Smith K., Fernandez-Mateos J., Yara-Romero E., Oliveira EA., Milite S., Caravagna G., James CT., Elia G., Berner A., Ryan Choi C-H., Ramagiri P., Chauhan R., Matthews N., Murphy J., Antoniou A., Clark SK., Mitchison M., Chin Aleong J-A., Domingo E., Spiteri I., McDonald SAC., Shibata D., Laclé MM., Wang LM., Moorghen M., Tomlinson IPM., Novelli M., Jansen M., Watson A., Valeri N., Wright NA., Bridgewater JA., Rodriguez-Justo M., Barnes CP., Kocher HM., Leedham SJ., Sottoriva A., Graham TA.
Aneuploidy is near-ubiquitous in cancer and contributes to tumor biology. However, the temporal evolutionary dynamics that select for aneuploidy remain uncharacterized. We performed longitudinal genomic analysis of 755 samples from 167 patients with colorectal-derived neoplasias from different stages through metastasis and treatment. Adenomas had few copy number alterations (CNA) and most were subclonal, whereas cancers had many clonal CNAs, suggesting that progression goes through a CNA bottleneck. Individual colorectal cancer glands from the same tumor had similar karyotypes, despite evidence of ongoing instability at the cell level. CNAs in metastatic lesions, after therapy, and in late recurrences were similar to the primary. Mathematical modeling indicated that these data are consistent with the action of negative selection on CNAs that "trap" cancer genomes on a fitness peak characterized by specific CNAs. Hence, progression to colorectal cancer requires traversing a rugged fitness landscape, whereas subsequent CNA evolution is constrained by negative selection.SignificanceWe profiled 167 long-term responders longitudinally (755 samples), documenting long-term cancer evolution. We found that a genetic bottleneck is required for progression and is associated with dramatic increase in CNAs but decrease in clonal diversity. After initiation, copy number evolution is constrained by negative selection through metastasis and treatment.