Optimizing Ultrasensitive DNA methylation detection for lung cancer and other malignancies

This proposal for a Biomarker Characterization Center (BCC) for the Early Detection Research Network (EDRN) seeks to improve the management of lung cancer through detection of cancerspecific DNA methylation. This effort includes a Biomarker Development Laboratory (BDL) which will optimize the methylation detection methods, implementation of these methods for clinical use through a Biomarker Reference Laboratory (BRL) with a longstanding record of molecular testing in a clinical setting, and an Administrative Core facilitating the interactions between the BDL and BRL, and with other EDRN investigators and the NCI. Previous work by the applicants has demonstrated the potential of DNA methylation detection for cancer diagnostics, and they have developed extremely sensitive assays for the detection of hypermethylated DNA sequences and optimized the isolation and processing of circulating cell-free DNA from tumors for these novel assays. The approach has been used to detect circulating cancer-specific DNA methylation changes for the early diagnosis of lung cancer in patients with screen-detected pulmonary nodules. Although sensitivity and specificity of the assay are promising, additional improvements in the performance are required for implementation of this approach in the setting of cancer screening. In this BCC, detection of cancer-specific DNA methylation changes in the plasma will be further improved, and new approaches developed and implemented to address the challenges of ultrasensitive detection of DNA methylation in the blood. In addition, we will assess the potential of these methods to detect other common and lethal malignancies. Our bioinformatic analysis of DNA methylation from The Cancer Genome Atlas (TCGA) has identified novel highly frequent cancer-specific methylation events common to all cancers, including lung cancer, that will be developed into universal cancer detection assays. The use of TCGA data has also resulted in the identification of other methylation alterations that allow determination of the origin (organ site) of this cancer-specific signal. The combination of optimal sample processing, ultrasensitive methylation detection, developed with universal cancer and histology specific loci detection, will allow improved lung cancer early detection in the setting of CT screening and management of detection of other cancer-specific DNA methylation from blood.