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A matter of methylation
BETHESDA, Md.—One of the key issues of diagnosing and treating cancer is the heterogeneity of the disease; with different subtypes resulting from different mutations, it is difficult to identify a single target with applicability in more than one form of cancer. But researchers at the National Institutes of Health (NIH) have discovered a genomic signature in tumor DNA that is found in five different types of cancer, with evidence that it may be present in even more cancer types. The results of their work appeared in The Journal of Molecular Diagnostics on Feb. 5.
The signature in question is the result of DNA methylation, which controls the expression of genes—higher amounts of DNA methylation, also known as hypermethylation, decrease a gene's activity.
“Finding a distinctive methylation-based signature is like looking for a spruce tree in a pine forest,” said Dr. Laura Elnitski, a computational biologist in the Division of Intramural Research at NIH’s National Human Genome Research Institute (NHGRI). “It’s a technical challenge to identify, but we found an elevated methylation signature around the gene known as ZNF154 that is unique to tumors.” Elnitski is head of the Genomic Functional Analysis Section and senior investigator in the Translational and Functional Genomics Branch at NHGRI.
Elnitski's team first discovered a methylation signature surrounding ZNF154 in 2013, when it was identified in 15 tumor types in 13 different organs using DNA samples from solid tumors. This recent study saw the team develop a series of steps that revealed methylation marks in colon, lung, breast, stomach and endometrial cancers, with all five tumor types and subtypes presenting with the same methylation mark around ZNF154. The tumor DNA, which had been amplified using PCR, was sequenced by the NIH Intramural Sequencing Center, and the results showed elevated methylation levels surrounding ZNF154 in all sequenced tumor types. Elnitski noted that the team was “so excited when we found this candidate biomarker. It’s the first of its kind to apply to so many types of cancer.”
In order to further confirm the connection between hypermethylation and cancer, the team developed a computer program that could assess methylation marks in the DNA of individuals with and without cancer, and were able to predict a threshold for detecting tumor DNA. They found that even when the amount of methylated molecules were reduced by 99 percent, the computer was still capable of detecting cancer-related methylation marks.
Elnitski's team also calculated the proportions of circulating tumor DNA that could be found in the blood, and moving forward, will begin screening blood samples from patients with bladder, breast, colon, pancreatic and prostate cancers to determine their program's accuracy of detection at low levels of circulating DNA. Tumor DNA in a cancer patient generally makes up 1 to 10 percent of all DNA circulating in the bloodstream, and when 10 percent of the circulating DNA contains the tumor signature, the researchers said their detection rate is encouraging.
There are still more questions to be answered regarding this research. Scientists aren't certain what ZNF154's role is in the body, and the connection between elevated DNA methylation and tumors is unknown. But Elnitski said that this work has “laid the groundwork for developing a diagnostic test, which offers the hope of catching cancer earlier and dramatically improving the survival rate of people with many types of cancer.”
The team will be testing that approach in concert with Dr. Christina Annunziata, an investigator in the Women's Malignancies Branch and head of the Translational Genomics Section at NIH’s National Cancer Institute. Together, the group will test blood samples from women with ovarian cancer to validate the NIH team's process over the course of treatment and assess if this type of analysis can offer improved detection of a recurrence.
“Ovarian cancer is difficult to detect in its early stages, and there are no proven early detection methods,” said Annunziata. “We need a reliable biomarker for detecting the disease when a cure is more likely. We are looking forward to testing Dr. Elnitski’s novel approach using DNA methylation signatures.”
SOURCE: NIH press release