No abstract

Background:The clinical course of World Health Organisation grade II gliomas remains variable and their time point of transformation into a more malignant phenotype is unpredictable. Identification of biological markers that can predict prognosis in individual patients is of great clinical value. PROX1 is a transcription factor that has a critical role in the development of various organs. PROX1 has been ascribed both oncogenic and tumour suppressive functions in human cancers. We have recently shown that PROX1 may act as a diagnostic marker for high-grade gliomas. The aim of this study was to address the prognostic value of PROX1 in grade II gliomas.Methods:A total of 116 samples were evaluated for the presence of PROX1 protein. The number of immunopositive cells was used as a variable in survival analysis, together with established prognostic factors for this patient group.Results:Higher PROX1 protein was associated with poor outcome. In the multivariate analysis, PROX1 was identified as an independent factor for survival (P=0.024), together with the presence of mutated isocitrate dehydrogenase 1 R132H protein, and with combined losses of chromosomal arms 1p/19q in oligodendrocytic tumours.Conclusion:PROX1 is a novel predictor of survival for grade II gliomas.

Recent studies suggest that the regulatory networks controlling the functions of stem cells during development may be abnormally active in human cancers. An embryonic stem cell (ESC) gene signature was found to correlate with a more undifferentiated phenotype of several human cancer types including gliomas, and associated with poor prognosis in breast cancer. In the present study, we used tissue microarrays of 80 low-grade (WHO Grade II) and 98 high-grade human gliomas (WHO Grades III and IV) to investigate the presence of the ESC-related proteins Nanog, Klf4, Oct4, Sox2 and c-Myc by immunohistochemistry. While similar patterns of co-expressed proteins between low-and high-grade gliomas were present, we found up-regulated protein levels of Nanog, Klf4, Oct4 and Sox2 in high-grade gliomas. Survival analysis by Kaplan-Meier analysis revealed a significant shorter survival in the subgroups of low-grade astrocytomas (n 5 42) with high levels of Nanog protein (p 5 0.0067) and of Klf4 protein (p 5 0.0368), in high-grade astrocytomas (n 5 85) with high levels of Nanog (p 5 0.0042), Klf4 (p 5 0.0447), and c-Myc (p 5 0.0078) and in glioblastomas only (n 5 71) with high levels of Nanog (p 5 0.0422) and of c-Myc (p 5 0.0256). In the multivariate model, Nanog was identified as an independent prognostic factor in the subgroups of low-grade astrocytomas (p 5 0.0039), high-grade astrocytomas (p 5 0.0124) and glioblastomas only (p 5 0.0544), together with established clinical variables in these tumors. These findings provide further evidence for the joint regulatory pathways of ESC-related proteins in gliomas and identify Nanog as one of the key players in determining clinical outcome of human astrocytomas.Gliomas are the most common primary tumors of the CNS and are divided into low-grade and high-grade gliomas. 1 Lowgrade gliomas (LGG) in adults are of malignancy Grade II, according to the WHO classification of brain tumors, and commonly occur as astrocytomas, oligodendrogliomas or oligoastrocytomas Grade II. In spite of a relatively favorable prognosis, LGG will eventually transform into high-grade tumors with fatal outcome. 2 High-grade gliomas (HGG) are of Grades III or IV according to the WHO classification. Grade III tumors are referred to as anaplastic gliomas and grade IV is also known as glioblastoma. 1 WHO Grade III tumors of an astrocytic phenotype are highly proliferative, infiltrative tumors but without necrotic areas and/or hyperplastic vasculature, whereas both anaplastic oligodendrogliomas and glioblastomas

The presence and termination of early seizure manifestations may be favourable prognostic factors in patients with low-grade gliomas.