PROX1 is a novel pathway-specific prognostic biomarker for high-grade astrocytomas; results from independent glioblastoma cohorts stratified by age and IDH mutation status

// Kenney R. Roodakker 1,* , Tamador Elsir 1,2,* , Per-Henrik D. Edqvist 3,4 , Daniel Hägerstrand 2 , Joseph Carlson 2 , Malgorzata Lysiak 5 , Roger Henriksson 6,7 , Fredrik Pontén 3,4 , Johan Rosell 8 , Peter Söderkvist 9 , Roger Stupp 10 , Elena Tchougounova 3 , Monica Nistér 2 , Annika Malmström 9,** and Anja Smits 1,11,** 1 Department of Neuroscience, Neurology, Uppsala University, University Hospital, Uppsala, Sweden 2 Department of Oncology-Pathology, Karolinska Institutet, Cancer Center Karolinska R8:05, Karolinska University Hospital, Stockholm, Sweden 3 Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden 4 Science for Life Laboratory, Uppsala University, Uppsala, Sweden 5 Department of Cell Biology, Linköping University, Linköping, Sweden 6 Department of Radiation Sciences & Oncology, Umeå University Hospital, Umeå, Sweden 7 Regional Cancer Center, Stockholm Gotland, Stockholm, Sweden 8 Regional Cancer Center South East Sweden and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden 9 Department of Advanced Home Care and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden 10 Department of Oncology, University Hospital Zurich, Zurich, Switzerland 11 Department of Clinical Neuroscience and Rehabilitation, Institute of Neuroscience and Physiology, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden * These authors have contributed equally to this work ** These authors share senior responsibility Correspondence to: Kenney R. Roodakker, email: // Keywords : PROX1; malignant astrocytomas; IDH mutations; primary glioblastomas; secondary glioblastomas; Gerotarget Received : February 22, 2016 Accepted : September 02, 2016 Published : September 10, 2016 Abstract PROX1 is a transcription factor with an essential role in embryonic development and determination of cell fate. In addition, PROX1 has been ascribed suppressive as well as oncogenic roles in several human cancers, including brain tumors. In this study we explored the correlation between PROX1 expression and patient survival in high-grade astrocytomas. For this purpose, we analyzed protein expression in tissue microarrays of tumor samples stratified by patient age and IDH mutation status. We initially screened 86 unselected high-grade astrocytomas, followed by 174 IDH1-R132H1 immunonegative glioblastomas derived from patients aged 60 years and older enrolled in the Nordic phase III trial of elderly patients with newly diagnosed glioblastoma. Representing the younger population of glioblastomas, we studied 80 IDH -wildtype glioblastomas from patients aged 18-60 years. There was no correlation between PROX1 protein and survival for patients with primary glioblastomas included in these cohorts. In contrast, high expression of PROX1 protein predicted shorter survival in the group of patients with IDH -mutant anaplastic astrocytomas and secondary glioblastomas. The prognostic impact of PROX1 in IDH -mutant 1p19q non-codeleted high-grade astrocytomas, as well as the negative findings in primary glioblastomas, was corroborated by gene expression data extracted from the Cancer Genome Atlas. We conclude that PROX1 is a new prognostic biomarker for 1p19q non-codeleted high-grade astrocytomas that have progressed from pre-existing low-grade tumors and harbor IDH mutations.