Abstract B79: Integrative quantitative analysis of pancreatic ductal adenocarcinoma mRNA, miRNA, and methylation profiles reveals interactions that are dependent on tumor cellularity
Authors: Telonis Aristeidis G. 
Published: December 2016

The Cancer Genome Atlas (TCGA) Pancreatic Adenocarcinoma (PAAD) consortium has conducted multilevel molecular profiling of 150 PAAD cases, including mRNA, miRNA, and methylation profiles. PAAD tumors are highly heterogeneous characterized by the significant presence of stromal cells and therefore by low tumor cellularity or tumor purity. This high tumor heterogeneity complicates genomic analysis of the tumor. Here, we investigated whether there are purity-specific interactions in the PAAD cohort of samples integrating mRNA, miRNA and methylation information.

The 150 subjects analyzed comprised of two almost equally sized tumor groups defined as having “low” (n=74) or “high” (n=76) purity and were analyzed separately to identify purity-specific interactions. Leveraging the TCGA transcriptomic and epigenomic data from these groups, we conducted correlation analyses to identify statistically significant miRNA-mRNA anti-correlations as well as among all miRNAs/mRNAs and the methylation probes in close proximity. Using computational miRNA target predictions, we identified potential miRNA:mRNA interactions between the miRNA-mRNA anti-correlated pairs.

Our findings describe a distinct regulatory landscape in each of the two purity groups. The interaction networks followed power-law distributions with specific miRNAs serving as the hubs of the scale-free networks. In the “low” purity group, miR-21-5p was identified to be a major hub, while the “high” purity network had miRNAs from both arms of miR-192 and miR-194 serving as the main hubs. These miRNAs were differentially regulating the transcriptome in each tumor group, as the differentially expressed transcripts between the two tumor groups were important components of the networks. The methylome impact on the transcriptome was found to have two components: one that is tumor-purity-dependent and one that is not dependent on purity. The former was the strongest as the majority of the methylation-mRNA/miRNA anti-correlations were distinct in the two groups.

The above results describe a purity-specific interaction map and highlight the importance of the stroma cells as regulators of the tumor genomic regulatory landscape. They further shed light on the dynamics of the pancreatic adenocarcinomas as they designate purity-specific regulatory axes that can be targetable. These signatures can increase our understanding pancreatic ductal adenocarcinoma and lead to improved patient outcomes.

Citation Format: Aristeidis G. Telonis, on behalf of The Cancer Genome Atlas Research Network.{Authors}. Integrative quantitative analysis of pancreatic ductal adenocarcinoma mRNA, miRNA, and methylation profiles reveals interactions that are dependent on tumor cellularity. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B79.