A Big Bang model of human colorectal tumor growth.
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Date
2015-03-01Author
Sottoriva, A
Kang, H
Ma, Z
Graham, TA
Salomon, MP
Zhao, J
Marjoram, P
Siegmund, K
Press, MF
Shibata, D
Curtis, C
Type
Journal Article
Metadata
Show full item recordAbstract
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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Subject
Humans
Colorectal Neoplasms
Cell Growth Processes
Genetic Heterogeneity
Models, Biological
Models, Genetic
Language
eng
Date accepted
2015-01-12
License start date
2015-03
Citation
Nature genetics, 2015, 47 (3), pp. 209 - 216
Publisher
NATURE PUBLISHING GROUP