A Big Bang model of human colorectal tumor growth

Andrea Sottoriva, Haeyoun Kang, Zhicheng Ma, Trevor A Graham, Matthew P Salomon, Junsong Zhao, Paul Marjoram, Kimberly Siegmund, Michael F Press, Darryl Shibata, Christina Curtis
2015 Nature Genetics  
What happens in the early, still undetectable human malignancy is unknown because direct observations are impractical. Here we present and validate a "Big Bang" model, whereby tumors grow predominantly as a single expansion producing numerous intermixed sub-clones that are not subject to stringent selection, and where both public (clonal) and most detectable private (subclonal) alterations arise early during growth. Genomic profiling of 349 individual glands from 15 colorectal tumors revealed
more » ... e absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone mixing in distant regions, as postulated by our model. We also verified the prediction that most detectable ITH originates from early private alterations, and not from later clonal expansions, thus exposing the profile of the primordial tumor. Moreover, some tumors appear born-to-be-bad, with sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications. Sottoriva et al.
doi:10.1038/ng.3214 pmid:25665006 pmcid:PMC4575589 fatcat:2oxig2iuhbabhel2ky24mw4pxy