Abstract 2522: RNA rescue somatic mutations and RNA editing in esophageal cancer
Authors: Radenbaugh Amie J. , Sanborn J Zachary , Newton Yulia , Vaske Charlie , Loon Katherine Van , Collisson Eric 
Published: August 2019

Abstract
The detection of somatic single nucleotide variants is a crucial component to the characterization of the cancer genome. Traditional mutation calling algorithms have focused on comparing the normal and tumor DNA from the same individual. For projects like The Cancer Genome Atlas (TCGA), it became routine to also sequence the tumor RNA. Our computational method, RADIA (RNA and DNA Integrated Analysis), combines the patient-matched normal and tumor DNA with the tumor RNA to detect somatic mutations. The inclusion of the RNA increases the power to detect somatic mutations, especially at low DNA allelic frequencies or when tumor purity is low. By integrating an individual’s DNA and RNA, we are able to detect mutations that would otherwise be missed by traditional algorithms that examine only the DNA. Mutations with high support in the RNA and low support in the DNA are termed RNA Rescue mutations. RNA editing is a post-transcriptional modification of pre-mRNA that has recently been identified as an additional epigenetic mechanism relevant to cancer development and progression. Using patient-matched normal and tumor DNA along with tumor RNA, we are able to identify RNA editing events across the entire transcriptome.
There exists a remarkable geographic variability observed in incidence rates for Esophageal Cancer where more than 80% of cases and deaths occur in developing countries. There is an urgent demand to address the unmet clinical needs for these regions. Mutation of the tumor suppressor gene TP53 is the most frequent genetic alteration in both Esophageal Squamous Cell Cancer (ESCC) and Esophageal Adenocarcinoma (EAC). In a previous study of 59 tumors in Malawi a high proportion of tumors without TP53 mutations was reported. Here, we apply RADIA to a cohort of 61 tumors from Tanzania, and identify RNA Rescue Mutations that were previously missed by DNA mutation callers in significantly mutated genes such as TP53, CDK6, NOTCH1, VEGFA, KMT2D. RNA Editing events in the 3’UTR regions of genes are very common, especially when Alu elements are present, and are known to deregulate microRNA mediated gene regulation. MDM2 is a key oncogene in the p53 pathway with elevated gene expression in many tumor types and is known to be transcriptionally repressed by microRNAs. Here we detect transcriptome-wide RNA Editing events, and identify RNA Editing events in the seed regions of microRNA target sites of genes such as MDM2. We will also show how RNA Editing of certain genes are significantly associated with an RNA-Seq clustering solution. These genes show significantly differential expression between RNA-Seq clusters, indicating that these editing events have a functional impact on the genes they affect. We will further investigate these functional effects and downstream implications on the molecular characterization of the RNA-Seq subtypes.
Citation Format: Amie J. Radenbaugh, J Zachary Sanborn, Yulia Newton, Charlie Vaske, Katherine Van Loon, Eric Collisson. RNA rescue somatic mutations and RNA editing in esophageal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2522.