Integrative Analysis of Hypoxia-Associated Signature in Pan-Cancer

Abstract

Summary Hypoxia is serving crucial roles in cancers. This study aims to comprehensively analyze the molecular features and clinical relevance of a well-defined hypoxia-associated signature in pan-cancer using multi-omics data. Data were acquired from TCGA, CCLE, GDSC, and GEO. RNA expression pattern, copy number variation (CNV), methylation, and mutation of the signature were analyzed. The majority of the 15 genes were upregulated in cancer tissues compared with normal tissue, and RNA expression was negatively associated with methylation level. CNV occurred in almost all the cancers, whereas mutation frequency was low across different cancer types. The signature was also closely related to cancer hallmarks and cancer-related metabolism pathways. NDRG1 was upregulated in kidney cancer tissues as indicated by immunohistochemistry. Besides, most of the 15 genes were risk factors for patients' overall survival. Our results provide a valuable resource that will guide both mechanistic and therapeutic analyses of the hypoxia signature in cancers.

Tumor Hypoxia Regulates Immune Escape/Invasion: Influence on Angiogenesis and Potential Impact of Hypoxic Biomarkers on Cancer Therapies

“…Recently, the genes themselves were interrogated through an integrative analysis that assessed the correlation between the expression of each of the 15 genes with their methylation status and copy number variations (CNVs), among other features, in pan-cancer data and in repositories of cancer cell lines ( 181 ). All genes presented with CNVs, and their expression levels were reflective of their decreased promoter methylation in most cancers.…”

“…All genes presented with CNVs, and their expression levels were reflective of their decreased promoter methylation in most cancers. Of relevance, the genes were associated with increased activation of oncogenic signaling pathways, and enrichment of malignant behaviors reflective of hypoxia, invasion and EMT ( 181 ). Furthermore, they acted as risk factors in more than half of gene-cancer pairs, supporting their cancer promoting role ( 181 ).…”

“…Of relevance, the genes were associated with increased activation of oncogenic signaling pathways, and enrichment of malignant behaviors reflective of hypoxia, invasion and EMT ( 181 ). Furthermore, they acted as risk factors in more than half of gene-cancer pairs, supporting their cancer promoting role ( 181 ). VEGFA , SLC2A1 , and LDHA are three of these genes that play central roles in angiogenesis ( VEGFA ) and glucose metabolism ( SLC2A1 and LDHA ) by encoding for VEGF, GLUT-1, and LDHA, respectively.…”

Tumor Hypoxia Drives Genomic Instability

“…Adaptation of cancer cells to hypoxia facilitates tumor aggressiveness via driving genomic instability ( Reynolds et al, 1996 ), tumor progression, and therapeutic resistance, thus resulting in poor prognosis ( Luoto et al, 2013 ; Zhang et al, 2020 ). Indeed, a recent study revealed that hypoxia increases the mutational burden of breast cancer cells, as reflected by elevated frameshift insertions and deletions ( Hassan Venkatesh et al, 2020 ).…”

Hypoxic Characteristic in the Immunosuppressive Microenvironment of Hepatocellular Carcinoma

“…In the process of adapting to the hypoxic TME, cancer cells acquire invasive and metastatic properties ( 16 ). Interestingly, this hypoxia-associated signature has impressive pan-cancer predictive potential ( 17 ). Hypoxia regulates the mitochondrial activity of HCC cells through the hypoxia-inducible factor (HIF)/hes related family bHLH transcription factor with YRPW motif 1/PTEN induced kinase 1 pathway ( 13 ).…”