Abstract
Extensive genome-wide analyses of deregulated gene expression have now been performed for many types of cancer. However, most studies have focused on deregulation at the gene-level, which may overlook the alterations of specific transcripts for a given gene. Clear cell renal cell carcinoma (ccRCC) is one of the best-characterized and most pervasive renal cancers, and ccRCCs are well-documented to have aberrant RNA processing. In the present study, we examine the extent of aberrant isoform-specific RNA expression by reporting a comprehensive transcript-level analysis, using the new kallisto-sleuth-RATs pipeline, investigating coding and non-coding differential transcript expression in ccRCC. We analyzed 50 ccRCC tumors and their matched normal samples from The Cancer Genome Altas datasets. We identified 7,339 differentially expressed transcripts and 94 genes exhibiting differential transcript isoform usage in ccRCC. Additionally, transcript-level coexpression network analyses identified vasculature development and the tricarboxylic acid cycle as the most significantly deregulated networks correlating with ccRCC progression. These analyses uncovered several uncharacterized transcripts, including lncRNAs FGD5-AS1 and AL035661.1, as potential regulators of the tricarboxylic acid cycle associated with ccRCC progression. As ccRCC still presents treatment challenges, our results provide a new resource of potential therapeutics targets and highlight the importance of exploring alternative methodologies in transcriptome-wide studies.
Highlights
Renal cancer is one of the ten most frequently occurring cancers found in both males and females in the United States [1]
We identified the global isoformspecific alterations in clear cell renal cell carcinoma (ccRCC) and explored the deregulated networks implicated in ccRCC progression
Using the kallisto-sleuth pipeline, we discovered 7,339 Differentially expressed transcript (DET) of which ~90% of the transcripts were derived from protein-coding genes
Summary
Renal cancer is one of the ten most frequently occurring cancers found in both males and females in the United States [1]. Most RCC tumors originate from the epithelial cells of proximal tubules within the cortex of the kidney, and RCCs carry with them several therapeutics challenges [3, 4]. Both chemotherapy and radiation treatments are largely ineffective, patients can be frequently asymptotic, and metastatic RCC has a relatively high 5-year mortality rate of > 90% [5]. As a result of elevated HIF proteins, changes to expression levels of several HIF responsive genes can occur, such as vascular endothelial growth factor (VEGF), MET protooncogene (c-MET), and transforming growth factor (TGF), altering the pro-angiogenic, invasive and proliferative characteristics of cancer cells. With the advent of largeplatform and high-throughout techniques, we have greatly improved our understanding of the VHL/HIF pathway, and we have expanded beyond this classical model to reveal other key molecular events that occur in ccRCC
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