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Sequence-Based Approach Used to Detect Endometrial Cancer Methylation Signature

NEW YORK (GenomeWeb) – An Ohio State University team has characterized the methylation patterns in endometrial cancer genomes, narrowing in on a methylation signature that appears to discriminate between so-called "high" and "low" methylator phenotypes.

The researchers used existing methylation data for 76 primary endometrioid endometrial cancer samples and a dozen normal endometrial samples, profiled with a methylated fragment capture sequencing strategy called MethylCap-seq. As they reported online yesterday in PLOS One, they then compared the resulting methylation patterns with array-based methylation profiles and other genomic information generated for the Cancer Genome Atlas effort.

"The purpose of this study was to develop a signature for methylation in endometrial cancer that distinguishes tumor from normal endometrium, and that has potential to classify tumors as having discrete levels of DNA methylation," senior author Paul Goodfellow, an obstetrics and gynecology researcher at Ohio State University, and his co-authors wrote.

Using the MethylCap-seq analysis, Goodfellow and his colleagues were able to uncover tumors with a methylator phenotype similar to a CpG island methylator phenotype (CIMP) described in colorectal cancer and other cancer types in the past. They also narrowed in on a methylation signature involving 13 regions of the endometrial cancer genome that lined up with enhanced mutation rates, mismatch DNA repair problems, and lower copy number changes in the TCGA samples.

That signature "distinguished tumors from both normal controls and adjacent normal tissue," the authors wrote, noting that it "could prove useful for detecting and classifying endometrioid endometrial carcinomas."

Generally speaking, the team's analysis suggested that the endometrial cancers had roughly twice as much promoter CpG island methylation as the normal endometrial tissue samples. Although the methylation levels were highly variable at nearly a third of the tumor CpG island sites profiled, the results pointed to nearly 2,300 overlapping CpG island sites with particularly enhanced methylation in group of tumors with high CpG island methylation.

By focusing in on parts of the genome with the most marked methylation differences between groups of tumors with higher or lower CpG island methylation, meanwhile, the researchers identified 16 CpG islands that were most highly methylated — a set that they narrowed down to the 13-region signature through follow-up methylation testing with Illumina's Infinium HumanMethylation 450 beadchip array.

In a collection of 11 endometrial tumors, the team reported, that methylation signature correctly identified five of the six tumors with high CpG island methylation. The five tumors with low CpG island methylation clustered together separately.

"Our analyses suggest that widespread promoter methylation is more prevalent in endometrioid endometrial cancer than previously appreciated," the authors concluded, "and that promoter methylation could be a useful marker for distinguishing tumors and normal tissue."