New insights into the earliest stages of colorectal tumorigenesis

Abstract

Tumors in the large intestine have been postulated to arise via a stepwise accumulation of mutations, a process that takes up to 20 years. Recent advances in lineage tracing and DNA sequencing, however, are revealing new evolutionary models that better explain the vast amount of heterogeneity observed within and across colorectal tumors. Areas covered: A review of the literature supporting a novel model of colorectal tumor evolution was conducted. The following commentary examines the basic science and clinical evidence supporting a modified view of tumor initiation and progression in the colon. Expert commentary: The proposed 'cancer punctuated equilibrium' model of tumor evolution better explains the variability seen within and across polyps of the colon and rectum. Small colorectal polyps (6-9mm) followed longitudinally by interval imaging with CT colonography have been reported to have multiple fates: some growing, some remaining static in size, and others regressing in size over time. This new model allows for this variability in growth behavior and supports the hypothesis that some tumors can be 'born to be bad' as originally postulated by Sottoriva and colleagues, with very early molecular events impacting tumor fitness and growth behavior in the later stages of the disease process.

Keywords: Big Bang model; CT colonography; colorectal cancer; punctuated equilibrium; tumor heterogeneity; tumorigenesis.

Figure 1

The cancer punctuated equilibrium model of colon tumor evolution better explains the variability of colorectal polyp growth. Computed tomography colonography (CTC) images from the initial (A) and final (B) scans from a patient with polyp that had an annual volumetric growth rate of 59% that was followed over 2.1 years prior to polypectomy. Black arrows point to the polyp that was followed longitudinally. (C) and (D) are possible evolutionary trajectories for a growing polyp. Shading under the line represent levels of intratumoral heterogeneity with punctuation events creating the greatest amount of heterogeneity. Tumorigenesis may begin with a punctuation event or periods of stasis and gradualism, a second punctuation event may provide enough molecular diversity allowing for malignant transformation. (E) and (D) are CTC images from the initial and final scans from a patient with polyp that had an annual volumetric growth rate of −33% that was followed over 0.9 years prior to polypectomy. (G) and (H) are possible evolutionary trajectories for a regressing polyp. Tumor regression may occur with the emergence of a negative or immunogenic phenotype acquired during a period of gradualism or via a punctuation event.