A 7 Gene Set Associated with Chronic Hypoxia of Prognostic Importance in Hepatocellular Carcinoma

PURPOSE: Hepatocellular carcinomas (HCC) have an unpredictable clinical course and molecular classification can provide better insight in prognosis and patient directed therapy. We hypothesized that in HCC certain microenvironmental regions exist with a characteristic gene expression related to chronic hypoxia which will induce aggressive behavior.EXPERIMENTAL DESIGN: We determined the gene expression pattern for human HepG2 liver cells under chronic hypoxia by microarray. Differentially expressed genes were selected and their clinical value was assessed. In our hypothesis-driven analysis we included available independent microarray studies of patients with HCC in one single analysis. Three microarray studies encompassing 272 patients were used as training sets to determine a minimal prognostic gene set and one recent study of 91 patients was used for validation. RESULTS: Using computational methods we identified 7 genes, out of 3592 differentially expressed under chronic hypoxia, that showed correlation with poor prognostic indicators in all training sets (65/139/73 patients) and this was validated in a 4th dataset (91 patients). Retrospectively the 7-gene set is associated with poor survival (HR 1.39, p=0.007) and early recurrence (HR 2.92, p=0.007) in 135 patients. Moreover, using a hypoxia score based on this 7-gene set we found that patients with a score >0.35 (n=42) had a median survival of 307 days, whereas patients with a score </=0.35 (n=93) had a median survival of 1602 days (p=0.005).CONCLUSIONS: We identified a unique, liver specific 7-gene signature associated with chronic hypoxia that correlates with poor prognosis in HCCs.status: publishe