Transcriptional landscape of DNA repair genes underpins a pan-cancer prognostic signature associated with cell cycle dysregulation and tumor hypoxia

Abstract

Overactive DNA repair contributes to therapeutic resistance in cancer. However, pan-cancer comparative studies investigating the contribution of all DNA repair genes in cancer progression employing an integrated approach have remained limited. We performed a multi-cohort retrospective analysis to determine the prognostic significance of 138 DNA repair genes in 16 cancer types (n = 16,225). Cox proportional hazards analyses revealed a significant variation in the number of prognostic genes between cancers; 81 genes were prognostic in clear cell renal cell carcinoma while only two genes were prognostic in glioblastoma. We reasoned that genes that were commonly prognostic in highly correlated cancers revealed by Spearman's correlation analysis could be harnessed as a molecular signature for risk assessment. A 10-gene signature, uniting prognostic genes that were common in highly correlated cancers, was significantly associated with overall survival in patients with clear cell renal cell (P < 0.0001), papillary renal cell (P = 0.0007), liver (P = 0.002), lung (P = 0.028), pancreas (P = 0.00013) or endometrial (P = 0.00063) cancers. Receiver operating characteristic analyses revealed that a combined model of the 10-gene signature and tumor staging outperformed either classifier when considered alone. Multivariate Cox regression models incorporating additional clinicopathological features showed that the signature was an independent predictor of overall survival. Tumor hypoxia is associated with adverse outcomes. Consistent across all six cancers, patients with high 10-gene and high hypoxia scores had significantly higher mortality rates compared to those with low 10-gene and low hypoxia scores. Functional enrichment analyses revealed that high mortality rates in patients with high 10-gene scores were attributable to an overproliferation phenotype. Death risk in these patients was further exacerbated by concurrent mutations of a cell cycle checkpoint protein, TP53. The 10-gene signature identified tumors with heightened DNA repair ability. This information has the potential to radically change prognosis through the use of adjuvant DNA repair inhibitors with chemotherapeutic drugs.

Keywords: Cell cycle; DNA repair; Hypoxia; Pan-cancer; Tumor microenvironment.