Transcriptomic profiling of Forkhead box transcription factors in adult glioblastoma multiforme.

Background: The Forkhead box transcription factor (FOX) family plays an essential role in embryogenesis, especially during brain development. Our hypothesis is that de-regulation of FOX genes may contribute to aggressive tumor biology and therapy resistance in patients with glioblastoma multiforme (GBM). Materials and Methods: Univariate and multivariate analyses were performed to evaluate prognostic significance of transcript levels of 31 FOX genes in a test set of GBM patients (n=191) and validated them in The Cancer Genome Atlas (TCGA) cohort comprising of 508 adult cases of GBM. The predictive significance of key FOX genes was investigated in patients who received chemotherapy or radiotherapy. Results: Low FOXA2 mRNA, low FOXN2 mRNA, low FOXN3 mRNA and high FOXG1 mRNA were associated with poor survival in the test and TCGA validation cohorts. In multivariate analysis, low FOXA2 mRNA, low FOXN2 mRNA, low FOXN3 mRNA and high FOXG1 mRNA remained independently associated with poor survival in the test and TCGA validation cohorts. In patients who received chemotherapy or radiotherapy, low FOXA2 mRNA, low FOXN2 mRNA and high FOXG1 mRNA correlated with adverse outcomes in the TCGA validation cohort. Conclusion: To our knowledge, our data provide the first comprehensive clinical evidence that FOXA2, FOXN2, FOXN3 and FOXG1 are promising biomarkers of GBM and warrant further investigation. Despite advances in surgery, chemotherapy and concurrent chemoradiotherapy strategies, the overall prognosis of patients with glioblastoma multiforme (GBM) remains poor, with a 3-year survival of less than 10% (1). Forkhead box transcription factors (FOX) are responsible for regulating the transcription of several proteins involved in embryogenesis, cell proliferation, differentiation, DNA repair and cell survival (2-4). There exist at least 50 known FOX genes in the human genome, categorised into 19 sub-groups (from A to S) (2-4). FOX genes may have a role in cancer pathogenesis. FOXOA1 has been linked to prostate cancer (5). Overexpression of FOXM1 has been identified in cancer of the liver, brain, and pancreas (6). FOXP1 may act as a tumor suppressor in breast cancer and paradoxically as an oncogene in certain types of lymphoma (7). In addition, FOXA1 and FOXG1 may also be involved in gliomagenesis (8, 9). We hypothesized that FOX genes may have a role in GBM pathogenesis.