Abstract
There is growing evidence that aberrant alternative splicing (AS) is highly correlated with driving tumorigenesis, but its function in kidney renal clear cell carcinoma (KIRC) remains to be discovered. In this study, we obtained the level-3 RNA sequencing and clinical data of KIRC from The Cancer Genome Atlas (TGCA). Combining with the splicing event detail information from TGCA SpliceSeq database, we established the independent prognosis signatures for KIRC with the univariate and multivariate Cox regression analyses. Then, we used the Kaplan-Meier analysis and receiver operating characteristic curves (ROCs) to assess the accuracy of prognosis signatures. We also constructed the regulatory network of splicing factors (SFs) and AS events. Our results showed that a total of 12029 survival-associated AS events of 5761 genes were found in 524 KIRC patients. All types of prognosis signatures displayed a satisfactory ability to reliably predict, especially in exon skip model which the area under curve of ROC was 0.802. Moreover, 18 splicing factors (SFs) highly correlated to AS events were identified. With the construction of the SF-AS interactive network, we found that SF powerfully promotes the occurrence of abnormal AS and may have a profound role in KIRC. Collectively, we screened survival-associated AS events and established prognosis signatures for KIRC, coupling with the SF-AS interactive network, which might provide a key perspective to clarify the potential mechanism of AS in KIRC.
Highlights
Renal cell carcinoma is the most comment histologic type of kidney cancer and about 70% are kidney renal clear cell carcinoma (KIRC) [1, 2]
46415 alternative splicing (AS) events for KIRC patients were detected in 10601 genes, which contained 3821 Alternate acceptor site (AA) in 2863 genes, 3270 Alternate donor site (AD) in 2300 genes, 8632 Alternate terminator (AT) in 3770 genes, 9509 APs in 3805 genes, 18117 Exon skip (ES) in 6915 genes, 235 Mutually exclusive exons (ME) in 227 genes, and 2831 Retained intron (RI) in 1902 genes by screening the AS events of KIRC (Figure 1(b))
The ES event was the most frequent AS events accounting for about 39%, while the ME event was rare among AS events of KIRC only accounting for about 0.5%
Summary
Renal cell carcinoma is the most comment histologic type of kidney cancer and about 70% are kidney renal clear cell carcinoma (KIRC) [1, 2]. The alternative splicing (AS) of pre-RNA is the key means and critical step in the gene expression regulation [4, 5]. An increasing number of studies focused on the potential regulatory mechanisms between tumors and ASs. For example, the splicing of FOX2 was observed to be changed in breast cancer that could regulate cancer cell proliferation [13]. Some studies showed that the deregulated expression of SFs can be found in cancer, such as the splicing factor SF2/ASF which is a puissant protooncogene that affects the regulation of alternative splicing of the vital target gene in various diseases [16], and the splicing factor SRSF10 is significantly upregulated in HPV16/18-positive cervical cancer and pivotal for the tumorigenic ability [17].
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