A Novel Machine Learning 13-Gene Signature: Improving Risk Analysis and Survival Prediction for Clear Cell Renal Cell Carcinoma Patients

Abstract

Patients with clear cell renal cell carcinoma (ccRCC) have poor survival outcomes, especially if it has metastasized. It is of paramount importance to identify biomarkers in genomic data that could help predict the aggressiveness of ccRCC and its resistance to drugs. Thus, we conducted a study with the aims of evaluating gene signatures and proposing a novel one with higher predictive power and generalization in comparison to the former signatures. Using ccRCC cohorts of the Cancer Genome Atlas (TCGA-KIRC) and International Cancer Genome Consortium (ICGC-RECA), we evaluated linear survival models of Cox regression with 14 signatures and six methods of feature selection, and performed functional analysis and differential gene expression approaches. In this study, we established a 13-gene signature (AR, AL353637.1, DPP6, FOXJ1, GNB3, HHLA2, IL4, LIMCH1, LINC01732, OTX1, SAA1, SEMA3G, ZIC2) whose expression levels are able to predict distinct outcomes of patients with ccRCC. Moreover, we performed a comparison between our signature and others from the literature. The best-performing gene signature was achieved using the ensemble method Min-Redundancy and Max-Relevance (mRMR). This signature comprises unique features in comparison to the others, such as generalization through different cohorts and being functionally enriched in significant pathways: Urothelial Carcinoma, Chronic Kidney disease, and Transitional cell carcinoma, Nephrolithiasis. From the 13 genes in our signature, eight are known to be correlated with ccRCC patient survival and four are immune-related. Our model showed a performance of 0.82 using the Receiver Operator Characteristic (ROC) Area Under Curve (AUC) metric and it generalized well between the cohorts. Our findings revealed two clusters of genes with high expression (SAA1, OTX1, ZIC2, LINC01732, GNB3 and IL4) and low expression (AL353637.1, AR, HHLA2, LIMCH1, SEMA3G, DPP6, and FOXJ1) which are both correlated with poor prognosis. This signature can potentially be used in clinical practice to support patient treatment care and follow-up.