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02-01-2012 | Genetics | Article

Methylated DNA biomarker could improve detection of ovarian cancer


Free abstract

MedWire News: Researchers have identified a blood-based aberrant DNA methylation marker of ovarian cancer that could enable detection of the disease when it is asymptomatic.

The biomarker, IFFO1-M, could also allow more sensitive detection of disease recurrence after tumor resection, they say.

Writing in the journal PLoS ONE, Peter Laird (University of Southern California, Los Angeles, USA) and colleagues describe development of a novel, large-scale systematic biomarker discovery and verification strategy to identify blood-based candidate DNA methylation markers that are not present in blood of women without ovarian cancer.

"Methylated DNA is chemically and biologically stable, readily detectable in many types of bodily fluids and therefore well-suited for blood-based cancer detection," they note.

The team first conducted a large-scale DNA methylation analysis of 41 ovarian cancer samples and two samples of peripheral blood leukocytes (PBLs) from disease-free postmenopausal women. This involved assessing the DNA methylation status of 27,578 probes spanning 14,489 unique genetic loci.

After ranking probes according to the difference in methylation levels between tumor and control samples, and confirming findings for the 15 top-ranked probes using an independent dataset (publicly available TCGA DNA methylation data on 284 serous ovarian cancer samples), the researchers then used more sensitive PCR-based DNA methylation detection platforms to narrow their focus onto eight probes with very low levels of DNA methylation in control PBL.

Further analysis of these eight probes in concentrated plasma DNA samples from 10 healthy postmenopausal women yielded just one marker - IFFO1 - with almost undetectable DNA methylation.

A highly sensitive assay of individually methylated DNA molecules detected the IFFO1 DNA methylation (IFFO1-M) marker in all serum samples from 16 ovarian cancer patients with advanced disease, compared with just two of eight serum samples from healthy older women controls. Receiver operating characteristic analysis indicated that IFFO1-M discriminated well between diseased and control serum samples, with an area under the curve of 0.95.

Finally, the team analyzed temporal patterns of IFFO1-M in comparison with those of the validated disease burden marker CA-125, in serial blood samples drawn before and after resection of the primary tumor in nine patients with high baseline IFFO1-M levels. Both CA-125 levels and IFFO1-M DNA methylation measurements dropped in the weeks after surgery in all samples; decreases in both markers paralleled the reduction in tumor burden. In addition, CA-125 and IFFO1-M levels combined tracked follow-up disease status in eight of the patients.

"These data strongly suggest that the IFFO1-M marker correlates with disease status and that it may complement CA-125 in detecting disease recurrence in some cases," Laird and colleagues write.

"We expect this marker and any additional candidate markers emerging from this discovery pipeline to have a great chance of success in future validation stages of the marker development process," they conclude.

By Caroline Price

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