Development and Verification of the Hypoxia-Related and Immune-Associated Prognosis Signature for Hepatocellular Carcinoma

BACKGROUND: It has been widely suggested that the association of hypoxia with the immune status within the microenvironment of hepatocellular carcinoma (HCC) is of great clinical significance. The present work was carried out aiming to establish the hypoxia-related and immune-associated gene signature to stratify the risks in HCC. PATIENTS AND METHODS: The ssGSEA and t-SNE algorithms were utilized to estimate the immune and hypoxia statuses, respectively, using the TCGA database-derived cohort transcriptome profiles. Different immune groups are distinguished according to the ssGSEA scores, while the hypoxia-high and -low groups are inferred based on the distinct overall survival (OS) of the two groups of patients. Moreover, prognostic genes were identified using the Cox regression model in combination with the LASSO approach, which were later used to establish the hypoxia-related and immune-associated gene signature. At the same time, an ICGC cohort was used for external validation. RESULTS: A total of 13 genes, namely, HAVCR1, PSRC1, CCNJL, PDSS1, MEX3A, EID3, EPO, PLOD2, KPNA2, CDCA8, ADAMTS5, SLC1A7 and PIGZ, were discovered by the LASSO approach for constructing a gene signature to stratify the risk of HCC. Those low-risk cases showed superior prognosis (OS) to the high-risk counterparts (p<0.05). Moreover, it was suggested by multivariate analysis that our constructed hypoxia-related and immune-associated prognosis signature might be used as the independent factor for prognosis prediction (p<0.001). Patients in high-risk groups had severe hypoxia, higher immune checkpoint expression such as PD-L1, and different immunocyte infiltration states (eg, higher infiltration of regulatory T cells in the high-risk group) compared with those low-risk patients. CONCLUSION: Our as-constructed hypoxia-related and immune-associated prognosis signature can be used as an approach to stratify the risk of HCC.