Construction of a Novel Multigene Panel Potently Predicting Poor Prognosis in Patients with Clear Cell Renal Cell Carcinoma

SIMPLE SUMMARY: Clear cell renal cell carcinoma (ccRCC) is the predominant cause of kidney cancer death attributed to its prevalence (70%) and its nature being the most aggressive form of kidney cancer. Most ccRCC deaths are resulted from metastasis. It is essential to know which ccRCCs are at risk of metastasis and the development to lethal disease; however, our capacity for such analysis remains poor. To improve this diagnostic capacity, we have examined a comprehensive ccRCC dataset containing 512 patients and have produced a 9-gene signature. This signature is novel; all its 9 components genes are unknown to be related to ccRCC. Importantly, all 9 individual genes possess significant ability in diagnosis of ccRCC metastasis and fatality; the combination of these genes or this signature predicts deadly ccRCCs at an impressive efficiency. This research will open new avenues in ccRCC research and will have a major impact in reducing ccRCC-associated deaths. ABSTRACT: We observed associations of IQGAP1 downregulation with poor overall survival (OS) in clear cell renal cell carcinoma (ccRCC). Differentially expressed genes (DEGs, n = 611) were derived from ccRCCs with (n = 111) and without IQGAP1 (n = 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, p < 2 × 10(−16), p = 1.08 × 10(−5), and p < 2 × 10(−16), respectively. SigIQGAP1NW independently associates with poor OS (HR 1.80, p = 2.85 × 10(−6)) 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 (n = 523) compared to non-tumor kidney tissues (n = 100). Collectively, we report a novel multigene panel that robustly predicts poor OS in ccRCC.