Bioinformatic Analysis of Progression of Colorectal Cancer
Posted: Monday, December 16, 2019
Colorectal cancer tumors seem to evolve with input from at least three different models, according to a study published in Genome Biology by Lixing Yang, PhD, of the University of Chicago, and colleagues. Although driver point mutations and genomic alterations responsible for chromosomal instability often occur early on during tumorigenesis, the authors highlighted that multiple evolutionary processes can occur within the same tumor, contributing to disease progression.
In this computational study, the authors used an integrative analysis to infer tumor purity, ploidy, and subclone structure from the whole-genome profiles of 63 patients with colorectal cancer from The Cancer Genome Atlas. They found that different mechanisms act on different genomic regions to optimize DNA dosage. Based on the timing of copy number variations, multiple independent instances of chromothripsis and kataegis could occur within a single tumor. (Chromothripsis, which is the phenomenon whereby up to thousands of clustered chromosomal rearrangements occur in a single event in confined genomic regions, has been known to be involved with both cancer and congenital diseases. Kataegis refers to a pattern of localized hypermutation noted in some cancer genomes.)
The authors proposed that at minimum, linear, parallel, and punctuated models of tumor evolution likely converge in colorectal cancer. In their model of colorectal tumor evolution, APC, KRAS, and TP53 mutations—along with arm-level copy losses, including loss of major tumor suppressors—may account for the main clonal expansion, followed by subclones undergoing non-neutral evolution, and, lastly, bursts of mutations.
“Our enhanced genetic model for colorectal cancer is substantially more comprehensive than the classical genetic model and offers further insights into the landmark events as well as their complexity in colorectal tumor progression,” concluded the authors.
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