P1.05-021 circRNAs: Potential Novel Biomarkers for the Early Detection of Lung Cancer

Abstract

Lung cancer is the leading cancer killer globally. Cancers such as colon, breast, and prostate all have relatively reliable early detection tests. In contrast, lung cancer does not. If caught early, lung cancer has a much better prognosis. Non-invasive or minimally invasive tools to improve early detection of lung cancer represents a critical unmet need. Analysis of the human transcriptome indicates that a mere 2% of the genome corresponds to protein coding transcripts, yet ∼ 75% of the genome is transcribed. It is now well established that these non-coding RNAs (ncRNAs) play important regulatory functions within the cell and their expression are often altered in cancer. Circular RNAs (circRNAs) are a species of ncRNAs. They are abundant, conserved and demonstrate cell-type specific expression patterns. Moreover, they are extremely stable with half-life’s greater than 48 hours, are resistant to degradation by RNA exonucleases, and have been shown to play important roles in cancer. Taken together these suggest that circRNAs could potentially be important biomarkers in early lung cancer diagnosis. Total RNAs isolated from a panel of matched normal/tumor NSCLC adenocarcinoma (Stage IA/IB) samples (n=6) were probed for circRNAs using the Arraystar circRNA microarray. Survival was assessed on linear mRNAs with associated circRNAs using KM-Plot. Interim analysis of the data has identified n=206 circRNAs with a 2-fold difference in expression between their matched normal vs. tumor counterparts. Principal Component Analysis (PCA) demonstrated a clear separation of the samples (Tumor vs. Normal). Self-Organizing Maps (SOMs) analysis generated distinctive SOMS clusters of circRNAs, while associated linear pathway enrichment for microRNA and transcriptional binding motifs identified several additional potential networks. Moreover, an analysis of linear mRNAs associated with 10 circRNAs with altered expression in adenocarcinomas found that these mRNAs were linked to overall survival, and that the majority were adenocarcinoma specific. Altered levels of a number of circRNAs were associated with lung adenocarcinoma. A separate cohort of squamous cell carcinomas is currently being assessed for circRNAs. At present we are validating the expression of these circRNAs in a larger cohort of specimens, and assessing whether or not these are detectable in plasma/serum from the same individuals. Overall, circRNAs may represent novel potential biomarkers for the detection of NSCLC, and may provide additional critical basic knowledge regarding the development and biology of NSCLC.