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Abstract
Abstract This presentation describes the clinical diagnostic use of a novel Bisulfite-free, Abscription-Based DNA methylation assay, MethylMeter, for analysis of grade 2, 3, & 4 gliomas. The proprietary 9 gene CpG-Island Methylation Phenotype (CIMP) profile was validated with bisulfite based MS-PCR and was then licensed by Castle Biosciences for commercialization as the DecisionDx-LGG Test. Very few CIMP assays have been transposed successfully into clinical diagnostic assays, since they depend on bisulfite-based technologies (MS-PCR or pyrosequencing). Bisulfite methods are not well suited to clinical applications which utilize formalin-fixed, paraffin-embedded (FFPE) tissues because of the large amount of sample that is required and the poor level of reproducibility that is inherent in bisulfite assays. We describe a more sensitive and quantitative alternative to MS-PCR for detection of the DecisionDx-LGG CIMP profile in FFPE tumors. The method, MethylMeter®, combines affinity separation of methylated and unmethylated DNA with a new target and signal amplification technology called CAP™ (Coupled Abscription®-PCR). Data will be presented demonstrating that MethylMeter® was able to successfully detect the appropriate DNA methylation patterns in FFPE patient samples for the 9 biomarkers utilized in the DecisionDx-LGG assay. Gliomas are stratified by histological grade, which is an indication of malignant potential and response to treatment. However, there is up to a 40% inter- and intra-observer histological grade variance rate in grading 2, 3, & 4 gliomas which is clinically signicant as histological grade determines treatment plan. A DecisionDx-LGG CIMP “positive” result is associated with significantly longer survival in patients with grade 2, 3, & 4 gliomas enabling improved treatment planning.I Initial attempts at CIMP profile analysis of glioma tumors using MS-PCR yielded clinically unacceptable results, substitution of the CAP-based MethylMeter assay enabled appropriate and clinically relevant analysis of CpG Island methylation levels in all 9 glioma tumor biomarkers. The MethylMeter assay results showed 100% concordance with the previous MS-PCR results. In contrast to the bisulfite-based assay, MethylMeter worked efficiently and reproducibly in FFPE patient samples, yielded increased levels of sensitivity, and was significantly faster. Data will also be presented showing that the quantitative data output provided by Abscription-based CAP assays provides a quantifiable readout of methylation levels that will enable future patient stratification, in contrast to the plus/minus readout provided by bisulfite assays. The data presented will be highly significant in paving the way for new MethylMeter-based CIMP pattern assays to be developed for diagnostic, theranostic, and companion diagnostic purposes. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5545. doi:1538-7445.AM2012-5545
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