Genome-wide Analysis of the Alternative Splicing Profiles Revealed Novel Prognostic Index for Kidney Renal Cell Clear Cell Carcinoma

Abstract

Alternative splicing (AS) is a major mechanism that greatly enhanced the diversity of proteome. Mounting evidence demonstrated that aberration of AS are important steps for the initiation and progression of human cancers. Here, we comprehensively investigated the association between whole landscape of AS profiles and the survival outcome of renal cell carcinoma (RCC) patients using RNA-seq data from TCGA SpliceSeq. Because of the limited number size of deaths in kidney chromophobe renal cell carcinoma (KICH) and papillary renal cell carcinoma (KIRP) TCGA cohorts, we only conducted survival analysis in kidney clear renal cell carcinoma (KIRC). We further constructed prognostic index (PI) based on prognosis-related AS events and built correlation network for splicing factors and prognosis-related AS events. According to the results, a total of 5351 AS events in 3522 genes were significantly correlated with the overall survival (OS) of kidney clear cell renal cell carcinoma (KIRC) patients. Seven of the PI models exhibited preferable prognosis-predicting capacity for KIRC with PI-ALL reaching the highest area under curve value of 0.875. The splicing regulatory network between splicing factors and prognosis-related AS events depicted a tangled web of relationships between them. One of the splicing factors: KHDRBS3 was validated by immunohistochemistry to be down-regulated in KIRC tissues. In conclusion, the powerful efficiency of risk stratification of PI models indicated the potential of AS signature as promising prognostic markers for KIRC and the splicing regulation network provided possible genetic mechanism of KIRC.

TF–RBP–AS Triplet Analysis Reveals the Mechanisms of Aberrant Alternative Splicing Events in Kidney Cancer: Implications for Their Possible Clinical Use as Prognostic and Therapeutic Biomarkers

“…Growing evidence indicates that alternative splicing is strongly associated with kidney cancer. For example, some specific alternative splicing events (ASEs) are potential prognostic biomarkers of kidney cancer [12], some ASEs were predicted to be associated with cancer stemness in KIRC [13], and a novel prognostic index based on prognosis-related AS events was revealed in KIRC [14]. However, comprehensively understanding the alterations of AS in KIRC remains unknown.…”

Significance and Possible Biological Mechanism for CLDN8 Downregulation in Kidney Renal Clear Cell Carcinoma Tissues

“…It is the third most prevalent malignant tumor of the urogenital system, following prostate (7.3%) and bladder cancers (3.0%) [ 1 , 2 ]. RCC is classified into several subtypes, including kidney renal clear cell carcinoma (KIRC), kidney chromophobe, and kidney renal papillary cell carcinoma, with KIRC being the most common, comprising about 70% of cases [ 3 , 4 ]. Nephrectomy, including radical and partial nephrectomy, remains the standard treatment for patients with localized RCC [ 5 ].…”