A Big Bang model of human colorectal tumor growth

Abstract

What happens in the early, still undetectable human malignancy 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 sub-clones 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 revealed the absence of selective sweeps, uniformly high intra-tumor heterogeneity (ITH), and sub-clone 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 sub-clone mixing indicative of early malignant potential. This new model provides a quantitative framework to interpret tumor growth dynamics and the origins of ITH with significant clinical implications.

Sexual dimorphism in cancer

“…An important notion is that cancer as a disease is not limited to a group of genetically deranged cells and their immediate environment, but is linked to general alterations in organ homeostasis as a result of perturbed developmental/morphogenetic signals and systemic factors 43,159 . Selection of cells with cumulative somatic mutations 160 or a "Big Bang" expansion of single cell populations with pre-existing dominant alterations 161 have been implicated in cancer development. However, there can be clonal expansion of cells harboring many cancer driver mutations without any clinical signs of the disease 162 .…”

Cancer evolution and heterogeneity

“…According to the model, we found that mutations in driver genes were clonal, and non‐driver genes were subclonal; therefore, advanced CRC showed ITH not by natural selection, but by neutral evolution. From the viewpoint of the early phase of evolution, Sottoriva et al9 reported that clonal expansions or selective sweeps are extremely rare after the transition to an advanced tumor as a result of the dynamics and spatial constraints of the rapidly growing population. They proposed a “Big Bang” model as a result of single clonal expansion in which the most detectable ITH occurs at a very early phase after the transition to an advanced tumor, and then these subclones expand without natural selection, while partially mixing, to eventually show uniformly high ITH in every region of the tumor.…”

“…1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35 This multiregional analysis (MRA) sequencing approach enabled us not only to observe spatial heterogeneity, but also to calculate temporal alterations and eventually disclose the evolution of tumors. There are two types of somatic aberration in a tumor: ubiquitous aberrations (founder mutations, trunk mutations, or clonal mutations) and scattered aberrations (progressor mutations, branch/leaf mutations, or subclonal mutations).…”

Six wedges to curing disease

“…For example, Sottoriva et al [24] considered the emergence and growth of competing clones in colorectal cancers. They showed that the initial appearance of a set of driver mutations resulted in the dominance of these clones in tumor growth, even when more fit strains subsequently emerged.…”