Identification of A‐B, a Novel Chimeric RNA in Colorectal Cancer

Abstract

Colorectal cancer (CRC) is the third leading cause of cancer‐related deaths worldwide, affecting more than one hundred thousand men and women in the United States every year. With the incidence of early‐onset (<50 years old) CRC increasing at an alarming rate, there is an urgent and unmet need for early biomarker discovery and the identification of novel therapeutic targets in CRC. Chimeric RNAs and their protein products are well‐established as ideal biomarkers and drug targets for malignant cancers, including BCR‐ABL in chronic myelogenous leukemia and EML4‐ALK in lung cancer. Using RNA‐seq data from The Cancer Genome Atlas (TCGA) database, we have identified a chimeric RNA, denoted as A‐B, present in 45.2% of CRC samples and just 17.6% of adjacent normal margin tissue, but absent in non‐cancer colon tissues. We determined that this chimeric RNA results from cis‐splicing between adjacent genes (cis‐SAGe), and includes a splice variant of the 5’ gene, altering the reading frame of the 3’ gene. This chimeric RNA encodes a novel transmembrane protein, with the alternate reading frame on the extracellular surface, making it an ideal target for antibody therapeutics. After generating an antibody to the chimeric protein and validating its use in immunoblotting, immunoprecipitation, and immunohistochemistry, we found this novel protein is present in patient CRC samples in a distinct, punctate pattern. Overexpression of this chimeric RNA resulted in increased cell proliferation, while siRNA mediated knockdown led to a reduction in cell proliferation. We are currently investigating the function of this chimeric RNA and its biomarker potential in clinical CRC samples.