Metastatic signaling of hypoxia-related genes across TCGA Pan-Cancer types

Abstract

Many primary-tumor subregions have low levels of molecular oxygen, termed hypoxia.Hypoxic tumors are at elevated risk for local failure and distant metastasis. Metastatic disease is the leading cause of cancer-related deaths and involves critical interactions between tumor cells and the microenvironment. Here we focused on elucidating the molecular hallmarks of tumor hypoxia that remains poorly defined. To fill this gap, we analyzed the genomic alterations and hypoxia score of 233 hypoxia-related genes of 6,343 individuals across 17 TCGA Pan-Cancer types. In addition, we analyzed a protein-protein interactome (PPi) network and the shortest paths from hypoxic proteins to metastasis. As results, mRNA high alteration was prevalent in all cancer types. Genomic alterations and hypoxia score presented a highest frequency in tumor stage 4 and positive metastasis status in all cancer types. The most significant signaling pathways were HIF-1, ErbB, PI3K-Akt, FoxO, mTOR, Ras and VEGF. The PPi network revealed a strong association among hypoxic proteins, cancer driver proteins and metastasis driver proteins. The analysis of shortest paths revealed 99 ways to spread metastasis signaling from hypoxic proteins. Additionally, we proposed 62 hypoxic genes strongly associated with metastasis and 27 of them with high amount of genomic alterations. Overall, tumor hypoxia may drive aggressive molecular features across cancer types. Hence, we identified potential biomarkers and therapeutic targets regulated by hypoxia that could be incorporated into strategies aimed at improving novel drug development and treating metastasis.

Identification of Key Proteins from the Alternative Lengthening of Telomeres-Associated Promyelocytic Leukemia Nuclear Bodies Pathway

“…PPi networks are fundamental resources to understand protein interactions among diseases [ 34 ]. Thus, we analyzed the 71 APBs-related proteins selected for our study by querying the STRING database [ 29 ].…”

TCGA Pan-Cancer Genomic Analysis of Alternative Lengthening of Telomeres (ALT) Related Genes

“…PPi networks are useful resources to understand how proteins interact between them in the cell [ 38 ], hence, the STRING database [ 32 ] was used to observe the interactions of 103 proteins. By using an interaction score of highest confidence (0.9) [ 33 ], a network was constructed; additionally, the most significant pathways ( p < 0.001) were selected and marked with different colors in the nodes ( Figure 5 a).…”

Expression profiles of hypoxia-related genes of cancers originating from anatomically similar locations using TCGA database analysis

“…Hypoxia induces metabolic and molecular changes in the majority of malignant tumors. The association between the genomic characteristics of hypoxia and aggressive tumor cell phenotypes is well-established (18). However, few studies have investigated the genetic profile of hypoxia-related genes of cancers originating from anatomically close organs and the genomic profiles from large scale.…”