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Diagnostic Technologies and Molecular and Cellular Profiling: Methylation Profiling, Epigenetics, and Chromatin Regulation

Global DNA methylation as a biomarker to screen asymptomatic individuals who are at-risk of developing lung cancer

AmberGen Inc, Waltham, MA, Vanderbilt Ingram Cancer Center, Nashville, TN, Boston University School of Medicine, Boston, MA

Abstract

A99

Lung cancer is the leading cause of cancer death for both men and women because symptoms of the disease usually present when it is at an advanced stage. Improved diagnosis will increase the survival rate, which currently is 15% over 5 years. With 45 million smokers in the US who are at-risk of developing the disease, there is an urgent need for a screening tool that can detect the early stages of lung cancer progression in the asymptomatic population.We have developed an assay, CpGlobal, which measures the global DNA methylation of the human genome. Global DNA methylation is measured by monitoring the sentinels of genome integrity, CpG dyads, which are markers for the susceptibility of developing cancer. Changes in methylation at these locales represent the earliest events in the progression toward a disease state. CpGlobal is performed in a 96 well format, requires <1µg of patient DNA and utilizes methyl sensitive enzymes as biomarkers for global DNA methylation. The analytical sensitivity of CpGlobal is ~5% and shows intra and inter sample reproducibility.Through the use of CpGlobal we have detected in lung cancer cell lines a high level of global hypomethylation (loss of methylation) that may represent a signature for the development and progression of this disease. The ability to monitor these changes in asymptomatic individuals (smokers and former smokers) may provide the early diagnostic tool that is missing in the armamentarium of screening methods currently available for lung cancer.We have applied CpGlobal on paired tumor and adjacent normal lung tissue samples, collected during surgical resection of the diseased lung from patients with Stage IA or IB lung cancer. The data indicated that the assay was both sensitive and specific at detecting changes in global DNA hypomethylation in the patient samples. These results indicate a role for CpGlobal as a potential screening tool for the early stage detection of lung cancer.CpGlobal has been utilized to measure the global DNA methylation in buccal cells, which are easily accessible, to create a non-invasive screening tool. The methylation status of this epithelial cell type has been shown to mirror the level that is observed in the lung. In a small study of smokers versus non-smokers we detected a significant difference in the global DNA methylation in the buccal cells from the two cohorts. These data would suggest that using CpGlobal to measure global DNA methylation in buccal cells may provide a non-invasive and sensitive means to monitoring asymptomatic individuals who are at-risk for developing lung cancer.