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Oct 15, 2010 (Vol. 30, No. 18)

Anticipating Protein Biomarker Applications

Nonlinear Path from Discovery to Validation Remains a Problem

  • Epigenetic Biomarkers

    Click Image To Enlarge +
    Orion Genomics’ MethylScope technology simultaneously measures the DNA methylation state of over 1 million loci across the human genome (left panel). MethylScreen, a quantitative PCR-based assay, provides precise measurements of DNA methylation content at specific sites in the genome. For example, hypermethylation of the GSHR gene, identified by MethylScope profiling and monitored in hundreds of samples by a MethylScreen assay, occurs in approximately 90% of breast tumors (right panel).

    Just about any part of the biological continuum from DNA to metabolites is being mined for novel biomarkers. Among them, DNA-methylation patterns are gaining more and more attention because of their broad implication in human disease. Epigenetic signals present a complex language that we are yet to understand.

    Since these signals are directly linked to DNA, they are believed to be causative rather than consequential of many downstream processes. In cancer studies, many lines of evidence point to the epigenetic contribution to cellular abnormalities. However, finding and understanding the patterns of epigenetic language is not trivial.

    Orion Genomics has developed several tools to efficiently and comprehensively measure epigenetic signals for the entire genome. MethylScope® reportedly enables genome-wide DNA-methylation profiling. Simultaneous study of the epigenetic state of every human gene as well as hundreds of thousands of other loci enables detection of candidate biomarkers that otherwise would remain undiscovered.

    MethylScope Array contains over 1 million spots each containing a unique 50 bp DNA sequence, together representing the human genome. Fluorescently labeled unmethylated and total genomic DNA differentially hybridizes to the array, resulting in a high-resolution quantitative methylation profile.

    “Finding causative methylation marks is only the first step in the process,” says Jared Ordway, Ph.D., vp of research and development. “We can continue their translation into clinical diagnostics by developing a specific assessment of the methylation density of that marker. But sometimes it makes more sense to measure the downstream result.” 

    With a collaborator, the company is conducting clinical validation of a predictive biomarker for increased risk of colorectal cancer. Forty percent of colon tumors have loss of imprinting (silencing) of the maternal copy of IGF2, insulin-like growth factor II gene. Expression of both copies of this gene is strongly linked with colon and 20 other cancer types. And while the appearance of this biomarker is caused by epigenetic changes, the clinical assay measures the allele-specific expression of IGF2.

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