Epigenetic silencing of HTATIP2 in glioblastoma contributes to treatment resistance by enhancing nuclear translocation of the DNA repair protein MPG.

Glioblastoma, the most malignant brain tumor in adults, exhibits characteristic patterns of epigenetic alterations that await elucidation. The DNA methylome of glioblastoma revealed recurrent epigenetic silencing of HTATIP2, which encodes a negative regulator of importin ß-mediated cytoplasmic-nuclear protein translocation. Its deregulation may thus alter the functionality of cancer-relevant nuclear proteins, such as the base excision repair (BER) enzyme N-methylpurine DNA glycosylase (MPG), which has been associated with treatment resistance in GBM. We found that induction of HTATIP2 expression in GBM cells leads to a significant shift of predominantly nuclear to cytoplasmic MPG, whereas depletion of endogenous HTATIP2 results in enhanced nuclear MPG localization. Reduced nuclear MPG localization, prompted by HTATIP2 expression or by depletion of MPG, yielded less phosphorylated-H2AX-positive cells upon treatment with an alkylating agent. This suggested reduced MPG-mediated formation of apurinic/apyrimidinic sites, leaving behind unrepaired DNA lesions, reflecting a reduced capacity of BER in response to the alkylating agent. Epigenetic silencing of HTATIP2 may thus increase nuclear localization of MPG, thereby enhancing the capacity of the glioblastoma cells to repair treatment-related lesions and contributing to treatment resistance.

Neuropsychological Outcomes after Surgery for Olfactory Groove Meningiomas.

BACKGROUND: In recent years, several studies have reported abnormal pre- and postoperative neuropsychological functioning in patients with meningiomas located in the prefrontal cortex (notably the ventromedial region). In the case of olfactory groove meningiomas, the tumor is in direct contact with the inferior aspect of the prefrontal cortex, a cortical region with crucial roles in decision-making, cognition and memory functions, potentially negatively impacting neuropsychological functions. MATERIALS AND METHODS: We retrospectively compared pre- and post-operative neuropsychological testing of 17 patients undergoing surgical removal of olfactory groove meningiomas in our institution between January 2013 and December 2018. Neuropsychological results were obtained from the patients' medical history and normalized as z-scores of their respective cognitive functions. RESULTS: Assessment of cognitive follow-up showed an important heterogeneity among patients. Pre-operative cognitive impairment was observed in most patients, particularly in cognitive flexibility (mean z-score: -1.35). Immediate post-operative cognitive status showed an overall impairment in all domains of cognition, significant for the domains of attention (p = 0.0273) and flexibility (p = 0.0234) and almost significant for the domain of language (p = 0.0547). The late follow-up at one year showed a trend towards general improvement, although attention and flexibility remained impaired. DISCUSSION: Olfactory groove meningiomas impact pre-frontal cortex cognitive functions, particularly in the domain of cognitive flexibility. After an initial postoperative worsening, patients tended to improve in most aspects after one year, aside from cognitive flexibility and attention.