A Big Bang model of human colorectal tumor growth

• Published in: Nature genetics Vol. 47; no. 3; pp. 209 - 216
• Main Authors: Sottoriva, Andrea, Kang, Haeyoun, Ma, Zhicheng, Graham, Trevor A, Salomon, Matthew P, Zhao, Junsong, Marjoram, Paul, Siegmund, Kimberly, Press, Michael F, Shibata, Darryl, Curtis, Christina
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2015; Nature Publishing Group
• Subjects: 14/32; 14/63; 45/22; 45/23; 45/43; 45/61; 631/114/2785; 631/208/212; 692/699/67/1504/1885/1393; Agriculture; Analysis; Animal Genetics and Genomics; Biomedicine; Cancer Research; Cell Growth Processes - genetics; Cloning; Colorectal cancer; Colorectal Neoplasms - genetics; Colorectal Neoplasms - pathology; Gene Function; Gene mutations; Genetic aspects; Genetic Heterogeneity; Genomes; Health aspects; Heterogeneity; Human Genetics; Humans; Models, Biological; Models, Genetic; Mutation; Tumors; United States
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.3214

Christina Curtis, Darryl Shibata and colleagues report genomic profiling of 349 individual glands sampled from 15 human colorectal tumors. They observe high within-tumor heterogeneity and mixing of subclones in distant tumor regions, supporting a model whereby tumor growth occurs predominantly as a single expansion, with most detectable subclonal mutations arising during the earliest phases of tumor growth. 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.