Development and validation of an individualized DNA repair-related gene signature in localized clear cell renal cell carcinoma.

BACKGROUND To establish a robust, individualized DNA repair-related gene signature to estimate prognosis for patients with localized clear cell renal cell carcinoma (ccRCC). MATERIALS AND METHODS We retrospectively analyzed gene expression profiles of 541 localized ccRCC patients from two public ccRCC cohorts. The DNA repair-related gene pair index (DRPI) was constructed with the least absolute shrinkage and selection operator (LASSO) regression model. The associations between DRPI, overall survival (OS), and disease-specific survival (DSS) were evaluated by Kaplan-Meier analysis, univariate analysis, and multivariate Cox regression survival analysis. We compared the predictive accuracy of different risk models with Harrel's C-index. RESULTS In the primary univariate analysis, patients in DRPI-high-risk group had significantly shorter OS [P < 0.001, HR (95% CI) 2.093 (1.431-3.061)] and DSS [P < 0.001, HR (95% CI) 3.567 (2.017-6.339)]. After adjusted for stage and grade, DRPI-high-risk group remained an independent adverse risk factor for both OS [P = 0.026, HR (95% CI) 1.629 (1.094-2.452)] and DSS [P = 0.010, HR (95% CI) 2.209 (1.217-4.010)]. DPRI showed comparable predictive accuracy with cell cycle proliferation (CCP) score and ccA/ccB signature. Copy number alterations and tumor mutation burden were enriched in DRPI-high tumors. There were elevated number of Treg cells and higher T cell exhaustion marker expression in DRPI-high-risk tumors. The combined DNA repair-clinical score outperformed other risk models in terms of C-index. CONCLUSION We validated the proposed DRPI as a predictor of clinical outcome in localized ccRCC patients. It provides an individualized and more accurate risk assessment beyond clinicopathological characteristics.