Dual prognostic role of 2-oxoglutarate-dependent oxygenases in ten cancer types: implications for cell cycle regulation and cell adhesion maintenance

Background: Tumor hypoxia is associated with metastasis and resistance to chemotherapy and radiotherapy. Genes involved in oxygen-sensing are clinically relevant and have significant implications for prognosis. In this study, we examined the pan-cancer prognostic significance of oxygen-sensing genes from the 2-oxoglutarate-dependent oxygenase family. Methods: A multi-cohort, retrospective study of transcriptional profiles of 20,752 samples of 25 types of cancer was performed to identify pan-cancer prognostic signatures of 2-oxoglutarate-dependent oxygenase gene family (a family of oxygen-dependent enzymes consisting of 61 genes). We defined minimal prognostic gene sets using three independent pancreatic cancer cohorts (n = 681). We identified two signatures, each consisting of 5 genes. The ability of the signatures in predicting survival was tested using Cox regression and receiver operating characteristic (ROC) curve analyses. Results: Signature 1 (KDM8, KDM6B, P4HTM, ALKBH4, ALKBH7) and signature 2 (KDM3A, P4HA1, ASPH, PLOD1, PLOD2) were associated with good and poor prognosis. Signature 1 was prognostic in 8 cohorts representing 6 cancer types (n =2627): bladder urothelial carcinoma (P=0.039), renal papillary cell carcinoma (P=0.013), liver cancer (P= 0.033 and P=0.025), lung adenocarcinoma (P=0.014), pancreatic adenocarcinoma (P< 0.001 and P=0.040), and uterine corpus endometrial carcinoma (P < 0.001). Signature 2 was prognostic in 12 cohorts representing 9 cancer types (n =4134): bladder urothelial carcinoma (P=0.039), cervical squamous cell carcinoma and endocervical adenocarcinoma (P = 0.035), head and neck squamous cell carcinoma (P=0.038), renal clear cell carcinoma (P=0.012), renal papillary cell carcinoma (P=0.002), liver cancer (P < 0.001, P <0.001), lung adenocarcinoma (P=0.011), pancreatic adenocarcinoma (P=0.002, P=0.018, P < 0.001), and gastric adenocarcinoma (P=0.004). Multivariate Cox regression confirmed independent clinical relevance of the signatures in these cancers. ROC curve analyses confirmed superior performance of the signatures to current tumor staging benchmarks. KDM8 was a potential tumor suppressor downregulated in liver and pancreatic cancers and an independent prognostic factor. KDM8 expression was negatively correlated with that of cell cycle regulators. Low KDM8 expression in tumors was associated with loss of cell adhesion phenotype through HNF4A signaling. Conclusion: Two pan-cancer prognostic signatures of oxygen-sensing genes were identified. These genes can be used for risk stratification in ten diverse cancer types to reveal aggressive tumor subtypes.