| Summary: | We observed associations of IQGAP1 downregulation with poor overall survival (OS) in clear cell renal cell carcinoma (ccRCC). Differentially expressed genes (DEGs, <i>n</i> = 611) were derived from ccRCCs with (<i>n</i> = 111) and without IQGAP1 (<i>n</i> = 397) reduction using the TCGA PanCancer Atlas ccRCC dataset. These DEGs exhibit downregulations of immune response and upregulations of DNA damage repair pathways. Through randomization of the TCGA dataset into a training and testing subpopulation, a 9-gene panel (SigIQGAP1NW) was derived; it predicts poor OS in training, testing, and the full population at a hazard ratio (HR) 2.718, <i>p</i> < 2 × 10<sup>−16</sup>, <i>p</i> = 1.08 × 10<sup>−5</sup>, and <i>p</i> < 2 × 10<sup>−16</sup>, respectively. SigIQGAP1NW independently associates with poor OS (HR 1.80, <i>p</i> = 2.85 × 10<sup>−6</sup>) after adjusting for a set of clinical features, and it discriminates ccRCC mortality at time-dependent AUC values of 70% at 13.8 months, 69%/31M, 69%/49M, and 75.3%/71M. All nine component genes of SigIQGAP1NW are novel to ccRCC. The inclusion of RECQL4 (a DNA helicase) in SigIQGAP1NW agrees with IQGAP1 DEGs enhancing DNA repair. THSD7A affects kidney function; its presence in SigIQGAP1NW is consistent with our observed THSD7A downregulation in ccRCC (<i>n</i> = 523) compared to non-tumor kidney tissues (<i>n</i> = 100). Collectively, we report a novel multigene panel that robustly predicts poor OS in ccRCC.
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