Impact of Genetic Targets on Primary Brain Tumor Therapy: What’s Ready for Prime Time?

Abstract

Primary brain tumors constitute a substantial public health problem with 66,290 cases diagnosed in the US in 2012, and 13,700 deaths recorded. With discovery of genetic factors associated with specific brain tumor subtypes, the goal of therapy is changing from treating a class of tumors to developing individualized therapies catering to the molecular composition of the actual tumor. For oligodendrogliomas, the loss of 1p/19q due to an unbalanced translocation improves both survival and the response to therapy, and is thus both a prognostic and a predictive marker. Several additional genetic alterations such as EGFR amplification, MGMT methylation, PDGFR activation, and 9p and 10q loss, have improved our understanding of the characteristics of these tumors and may help guide therapy in the future. For astrocytic tumors, MGMT is associated with a better prognosis and an improved response to temozolomide, and for all glial tumors, mutations in the IDH1 gene are possibly the most potent of good prognostic markers. Three of these markers - 1p/19q deletions, MGMT methylation status, and mutations in the IDH1 gene - are so potent that a new brain tumor subtype, the "triple negative" glioma (1p/19q intact, MGMT unmethylated, IDH1 non-mutated) has entered common parlance. Newer markers, such as CD 133, require additional investigation to determine their prognostic and predictive utility. In medulloblastomas, markers of WNT activation, MYCC/MCYN amplification, and TrkC expression levels are reliable prognostic indicators, but do not yet drive specific treatment selection. Many other proposed markers, such as 17q gain, TP53 mutations, and hMOF protein expression show promise, but are not yet ready for prime time. In this chapter, we focus on the markers that have shown convincing prognostic, predictive, and diagnostic value, and discuss potential markers that are being currently being intensively investigated. We also discuss serum profiling of tumors in an effort to discover additional potential markers.

Serum macrophage-derived chemokine/CCL22 levels are associated with glioma risk, CD4 T cell lymphopenia and survival time

“…IDH mutation, 1p19q codeletion and MGMT methylation are tumor markers that have been shown to be associated with improved prognosis in glioma patients. 39 We controlled for the effect of IDH mutation in most patients and 1p19q codeletion in patients with oligodendroglial tumors, but were not able to examine MGMT methylation. However, MGMT methylation is highly correlated with IDH status and we have IDH mutation results for most cases.…”

MicroRNA-134 modulates glioma cell U251 proliferation and invasion by targeting KRAS and suppressing the ERK pathway

“…A few risk factors could induce gliomas such as radiation hazards, use of exogenous hormone, consumption of coffee and tea, smoking status, and physical conditions [6][7][8]. Although aggressive surgery in conjunction with adjuvant therapy including chemotherapy and radiation have been introduced, prognosis of patients with malignant gliomas is still extremely poor, and glioma has been considered as a life-threatening disease which imposes enormous ongoing economic burdens on the health care system [9,10]. Therefore, it has been Yuguang Zhao and Dong Pang contributed equally to this work.…”

Reduced expression of microRNA-134 correlates with malignancy and poor prognosis in human glioma

“…Patients with anaplastic astrocytomas have a survival time of 2-3 years and patients with GBM even shorter survival [5]. Even after aggressive treatment, including maximal surgical resection, radiotherapy and chemotherapy, recurrence of GBM is common and survival time is only 12-15 months [6]. Therefore, early detection and efficient treatment strategies are vital for improving clinical outcomes of these patients.…”