A Big Bang model of human colorectal tumor growth

By A. Sottoriva, Haeyoun Kang, Zhicheng Ma, T. Graham, M. Salomon, Junsong Zhao, Paul Marjoram, K. Siegmund, M. Press, D. Shibata and 1 more. Nature Genetics, 2015

992 citations recorded by the source corpus.

What happens in early, still undetectable human malignancies 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 subclones 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 showed an absence of selective sweeps, uniformly high intratumoral heterogeneity (ITH) and subclone 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 subclone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH, with important clinical implications.

Subfields: Cancer Research, Modeling and Simulation, Pathology and Forensic Medicine

View Paper: https://www.semanticscholar.org/paper/e5711e881cceaec8ffe783a40bc3fa90855ef1a4

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Citations in the corpus

Subclonal diversification of primary breast cancer revealed by multiregion sequencing (2015, positive): “In colon cancer, there is evidence that the latter can explain observed patterns of subclonal heterogeneity 17 .”
CMScaller: an R package for consensus molecular subtyping of colorectal cancer pre-clinical models (2017, background): “This may be explained by intra-tumor heterogeneity 43,44 , both from immune/stromal infiltration (tumor cell percentage and stromal composition) and intrinsic to the cancer cells 45 .”
Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, positive): “Specifically, while evidence for selection of driver events in cancer development, as well as the selection pressures imposed by therapy, are undisputed, following a ‘big-bang’ of diversity early in tumor evolution, ITH development can follow the laws of neutral growth (Sottoriva et al., 2015).”