HIF-1α up-regulation is associated with adverse clinicopathological and biological factors in neuroblastomas

Aims: To study the expression of hypoxia-inducible factor 1 alpha (HIF-1 alpha) in clinical neuroblastoma (NB) samples and its association with the clinicopathological features, biological features and survival of NB patients. Methods and results: Immunohistochemistry indicated that elevated HIF-1 alpha expression was present in 30 of 90 (33%) NBs. This expression was correlated significantly and positively with higher clinical stage (P = 0.002), =18 months of age at presentation (P = 0.020), high-risk group (P = 0.005), unfavourable pathology (P = 0.002), MYCN amplification (P < 0.001), 1p deletion (P = 0.004) and 17q gain (P = 0.002). Enzyme-linked immunosorbent assays showed that total HIF-1 alpha protein was significantly higher in NBs of patients with all examined adverse prognostic factors except for age. Univariate survival analysis revealed that higher-than-median HIF-1 alpha total protein levels were associated significantly with a decrease in event-free survival (EFS) (P = 0.017), but not in overall survival (OS) (P = 0.12). HIF-1 alpha immunoexpression by =10% of tumour cells was associated significantly with decreased OS and EFS (P = 0.002 and P = 0.004, respectively), but not in multivariate analysis after adjusting for the high-risk group (P = 0.16 and P = 0.19, respectively). Conclusions: HIF-1 alpha was increased significantly in patients with NB associated with unfavourable characteristics. HIF-1 alpha is a prognostic indicator of poor OS and EFS and defines subgroups of NBs with aggressive clinical behaviour.