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

ABSTRACT

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.