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Nat Genet. 2015 Mar;47(3):209-16. doi: 10.1038/ng.3214. Epub 2015 Feb 9.

A Big Bang model of human colorectal tumor growth.

Author information

1
Department of Preventive Medicine, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.
2
1] Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA. [2] Department of Pathology, CHA University, Seongnam-si, South Korea.
3
1] Center for Evolution and Cancer, University of California, San Francisco, San Francisco, California, USA. [2] Centre for Tumor Biology, Barts Cancer Institute, Queen Mary University of London, London, UK.
4
Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.

Abstract

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.

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PMID:
25665006
PMCID:
PMC4575589
DOI:
10.1038/ng.3214
[Indexed for MEDLINE]
Free PMC Article

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