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Genetic, Epigenetic Factors Alongside Phenotypic Plasticity Influence Colorectal Cancer Evolution

NEW YORK — Genetic and epigenetic variations alongside phenotypic plasticity contribute to colorectal cancer tumor evolution and heterogeneity, a pair of new studies has found.

In the studies, which appeared in Nature on Wednesday, an international team of researchers generated sequencing, transcriptomic, and chromatin accessibility data for a series of colorectal cancer tumor samples to examine how genetic and epigenetic changes contribute to tumor evolution and heterogeneity, which can confound treatment efforts.

"I hope our work will change the way we think about cancer and its treatment — and should ultimately affect the way patients are treated," co-author professor Trevor Graham, director of the Centre for Evolution and Cancer at the Institute of Cancer Research in the UK, said in a statement. "Genetic testing for cancer mutations only gives us part of the picture about a person's cancer — and is blind to 'epigenetic' changes to how genes are read. By testing for both genetic and epigenetic changes, we could, potentially, much more accurately predict which treatments will work best for a particular person's cancer."

In the first study, the researchers examined 1,370 samples collected from 38 lesions isolated from 30 patients, with between 21 and 55 samples collected per patient. The samples underwent whole-genome sequencing, chromatin accessibility, and RNA-seq analysis. Of the patients, half had stage III CRC while 12 had stage II disease and three had stage I CRC.

As they spatially sampled the patients' tumors, the researchers were able to examine the clonal evolution of the disease. They found that mutations within chromatin modifier genes were stable, heritable, and under positive selection, and found a number of recurrent chromatin accessibility alterations. A number of these changes, the researchers noted, fell near the regulatory regions of known cancer driver genes.

These findings suggested to the researchers that epigenomic alterations likely influence key tumor phenotypes.

For instance, a number of the chromatin accessibility changes affected binding involving the CCCTC-binding factor, most often leading to a loss of accessibility, though a small group showed an increase in accessibility. Further, there were changes in accessibility affecting transcription factors involved in development, such as the HOX, FOX, and SOX families, indicating a role for developmental processes in tumor formation. These epigenomic changes additionally influenced the accumulation of somatic genetic mutations, the researchers found.

Meanwhile, in their second study, the researchers analyzed a set of nearly 300 samples from more than a dozen colorectal cancer tumors for which they also generated spatially resolved full-transcript RNA-seq data and for a subset of which they had paired genome sequencing and chromatin accessibility data.

They found that much of intratumor heterogeneity in gene expression was not strongly heritable. Instead, they uncovered evidence of phenotypic plasticity, or changes in gene expression that occur independent of the tumor's evolutionary history. Less than 1 percent of expressed genes and less that 5 percent of hallmark pathways exhibited strong evidence of heritability based on tumor evolution analyses.

Still, the researchers found that the tumors analyzed did have subclonal cells with at least one heritable alteration that led to a change in gene expression, but those alterations were not always associated with changes in fitness.

According to the researchers, their findings underscore the role of nongenetic factors in colorectal cancer development and that to fully understand patients' disease, these factors, too, need to be examined. They further could represent potential treatment targets.

"We have for the first time been able to map epigenetic changes alongside the accumulation of DNA mutations as a colorectal tumor evolves," co-author Andrea Sottoriva, head of the Computational Biology Research Centre at Human Technopole in Milan, said in statement. "This provides exciting opportunities to create new treatments for cancer that don't target the effects of DNA mutations, but instead the epigenetic changes which determine how genes are read."