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Team IDs Characteristic Epigenetic Enhancer Patterns in Colon Cancer

NEW YORK (GenomeWeb News) – Colon cancers carry a telltale set of epigenetic enhancer sites that appear to mediate gene expression shifts in the disease, according to a new online study in Science.

A Case Western Reserve University-led team used the genome-wide localization patterns for an enhancer-associated histone mark to help compare the enhancer patterns in a dozen colon cell lines — nine generated from colon cancers and three from normal colon tissue.

The search uncovered a set of so-called variant enhancer loci, or VELs, that are lost or gained in colon cancer samples in a way that flips certain genes on or off and produces characteristic colon cancer transcriptional patterns.

These VELs "are consistently found across multiple independent colon tumor samples, despite the fact that the tumors arose in different individuals and are at different stages of the disease," senior author Peter Scacheri, a genetics researcher at Case Western who is also affiliated with the Case Comprehensive Cancer Center, explained in a statement.

"The set of common VELs govern a distinct set of genes that go awry in colon cancer," he added.

Scacheri and his team used chromatin immunoprecipitation coupled with Illumina GAII to look at genome-wide binding sites for H3K4me1, a histone mark often found at enhancer elements.

By comparing H3K4me1 ChIP-seq results for nine colorectal cancer cell lines — two generated from early-stage tumors, two from late-stage tumors, and five from metastatic tumors — with results for three normal colon epithelial cell lines and nine lines representing other tissues types, the team was able to find sites in the genome where enhancer activity is higher or lower than usual in colon cancer.

From the tens of thousands of variant enhancer loci detected overall, researchers narrowed in on 2,604 extra VELs present in five or more of the colon cancer lines and 2,047 VELs that were lost in at least six of the cancer lines.

Almost all of these VELs turned up in at least two of the colorectal cancer cell lines. Across all nine of the cancer lines, meanwhile, the team found 197 VELs that were shared.

"The commonality of the epigenetic colon cancer signature captured by VELs contrasts with the marked heterogeneity in mutations in colon cancer candidate driver genes revealed by genome sequencing," they noted, "and suggests either that VELs capture pathway outputs that are downstream of sets of gene mutations or that they capture epigenetic alterations that are independent of and more common than gene mutations."

Even so, some of the sites in the genome where enhancer activity varied between normal and cancerous colon cells did overlap with loci linked to colon cancer through past genome-wide association studies.

These and other analyses suggested that "in colon cancer, the chromatin configuration is altered by acquisition of putative enhancer marks that are normally found in non-colon cell types," the study authors explained, "and loss of putative enhancer markers that typify normal [colon epithelial crypt cell] differentiation status; the net effect leading to a less colon specific phenotype."

As anticipated, these altered enhancer profiles coincided with altered expression of nearby genes in the colon cancer lines, the team found, though the expression effects appeared to be more dramatic for lost than for gained VELs.

Moreover, when they predicted which genes would have enhanced or muted expression based on the colon cancer VEL signature, the researchers came up with expression profiles that were remarkably similar to those seen in actual primary colorectal tumors.

Together, the team's findings hint that characteristic epigenetic enhancer marks in colon cancer cells not only contribute to the gene expression changes that help spur on the disease, but may also serve as molecular targets for detecting or trying to stave off such events.

Still, those involved in the study say more work is needed to determine whether it's feasible to consider exploiting VELs as a means of colon cancer treatment or prevention.

"The key next step will be to determine whether we can use VELs for 'personalized medicine,' to molecularly define distinct groups of colon cancers that differ in their clinical behavior, and to enable selection of specific drugs that will best treat a given colon tumor," Case Western's Sanford Markowitz, a co-author on the study, said in a statement.

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