A Big Bang Model of Human Colorectal Tumor Growth

Overview

Journal Nat Genet

Specialty Genetics

Date 2015 Feb 10

PMID 25665006

Citations 540

Authors

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

Affiliations

Soon will be listed here.

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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