The role and clinical significance of DNA damage response and repair pathways in primary brain tumors

In 2012, it is predicted that nearly 23,000 new primary brain tumors will be diagnosed, [1] of which 70% will be gliomas [2]. The most common type of glioma is glioblastoma multiforme (GBM), which accounts for 54% of all gliomas (42% of all primary brain tumors). Five-year survival is a dismal 4.70% for patients with GBM, [3] with a median survival time of just over 3 months following resection [4]. Despite a massive research effort, outcomes remain dismal in malignant brain tumors.Our limited understanding of the mechanisms which underlie brain tumorigenesis severely limit preventative and therapeutic options for patients. The current standard treatment for GBM involves surgical resection followed by adjuvant radiotherapy (RT), with or without concomitant chemotherapy [5]. Disappointingly, this regimen only affords GBM patients a median survival benefit of 14.6 months- a 12 month improvement over resection alone [4,6]. It is important to note that radio- and chemotherapies are, at the molecular level, based on inducing enough DNA damage in the tumor cell to result in lethality. Unfortunately, these therapies also cause DNA damage to surrounding neuronal tissue, resulting in a variety of local and systemic toxicities. With regard to ionizing radiation (IR) treatments to the brain, side effects can be severe and include nausea, vomiting, seizure, and permanent cognitive and focal neurological deficits [7].As such, there is a substantial research effort seeking to discover new therapeutic regimens that maximize tumor killing while minimizing these normal tissue toxicities, based on understanding of the differences in the behaviors and pathways of healthy and neoplastic cells. Current research and understanding of DNA damage response and repair (DRR) in glioma tumorigenesis and treatment response is the focus of this review.A critical feature of the eukaryotic cell is its ability to maintain genome stability across generations, attributed, in part, to the sophisticated