Genome-wide scan for epigenetic alterations in lung tumors reveals a novel list of powerful biomarkers.

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Epigenetic changes play an important role in tumorgenesis. The most frequently reported epigenetic alteration in cancer is a change in cytosine methylation. Such alterations affect the methylation of repetitive elements as well as methylation of single-copy gene associated CG-rich regulatory sequences (i.e. CpG islands), and are suspected to be among early events of tumorgenesis. Understanding of these epigenetic alterations could be clinically useful for the development of population screening diagnostics as well as for evaluating disease prognosis.

Lung cancer is the most deadly cancer for men and women. Because of absence of a reliable screening program, about 70% of lung tumors are diagnosed at late stage when survival is poor. Therefore, development of simple diagnostics tests is a priority in the fight against lung cancer. Considering that epigenetic alterations are stable and can be detected in bodily fluids, such tumor-specific changes could be a basis for developing powerful non-invasive tests for lung cancer.

Here, we described the results of the application of our proprietary microarray-based genome-wide DNA methylation analysis using patient matched lung adenocarcinoma and adjacent normal tissues in a scan of more than 21,000 genomic loci including nearly 80% of the annotated transcriptional start sites and more than 9,000 CpG islands. The discovery tissue panel consisted of 8 adenocarcinoma and 8 adjacent normal lung tissues. After the convergance of two parallel statistical analysis approaches, approximately 190 loci were nominated with the capacity to distinguish tumor and normal tissues based upon methylation state. These loci were independently analyzed by a quantitative PCR-based method in both the discovery and a secondary panel consisting of 30 tumor-adjacent normal pairs, as well as in blood and lung tissues of normal individuals (n=23 and n=22, respectively). This analysis resulted in a panel of 21 loci each of which has a clinical specificity (NPV) greater than 80% and clinical sensitivity (PPV) ranging from 60 - 89%. This panel is currently being evaluated in a larger tertiary panel. Results from the array analysis, the qPCR validation from all 38 patients and 45 controls, as well as bisulfite-genomic sequencing confirmation will be preseted. The potential values of these biomarkers for clinical diagnostic and prognostic products will be discussed.