Pan-Cancer Analysis of Expression, Mutation and Prognosis for Hypoxia-Inducible Factors (HIFs) and Their Regulators

Background: Hypoxia-inducible factors (HIFs) are the core regulator of cellular reaction during hypoxia, which also contribute to the development of cancer. We aimed to unravel the entire landscape of these factors in different types of cancer. Methods: The molecular alterations and clinical relevance of hypoxia related genes were systematically analysed in 33 cancer types. The expression, mutation, copy number variation, functional pathways, immune cell correlations and prognostic value were investigated. Findings: EGLN3 were highly expressed in most tumors; while EPAS1 and HIF3A showed low expression in most tumors. The average mutation frequency of HIFs ranged from 0% to 51.5%, of which CREBBP, EP300, HIF3A and EPAS1 showed high mutation frequencies. Besides, gastric and colorectal cancer cell lines showed frequent mutations of hypoxia related genes. ARNT showed widespread copy number amplification across various cancer types. Hypoxia related genes participated in cancer-related pathways including protein secretion, mitotic spindle, G2/M checkpoint, DNA repair, IL6/JAK/STAT3 signal and coagulation. CREBBP, HIF1A, EP300, ARNT, and EGLN1 demonstrated significant correlation with immune cell infiltration. Importantly, hypoxia related genes were significantly associated with survival of KIRC (kidney renal clear cell carcinoma). Interpretations: The expressions of hypoxia related genes demonstrated significant association with multiple oncogenic pathways and showed correlation with immune cells infiltration. Aberrant expression of hypoxia related genes could predict prognosis of cancer patients. These findings provide novel evidence for further investigation of hypoxia related genes in the development and therapy of cancer in the future. Funding Statement: This study is supported by grants from Public Welfare Foundation of Liaoning Province (No. 2015005002) and Fund for Scientific Research of The First Hospital Of China Medical University (FHCMU- FSR). Declaration of Interests: All of the authors declare that there is no conflict of interest. Ethics Approval Statement: Not required.