In adults, pilocytic astrocytomas (PA) account for less than 2% of gliomas, resulting in uncertainty regarding the clinical course and optimal treatment, particularly in cases where gross total resection (GTR) could not be achieved. Moreover, information on molecular markers and their prognostic impact is sparse. In order to improve risk stratification, we analyzed our institutional series of 58 patients aged 17 years and older with histology-proven intracranial PA World Health Organization grade I for clinical and molecular prognosticators. Anaplastic and NF1-associated tumors were excluded. O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was determined by pyrosequencing or 450k/850k DNA methylation array. A univariate log-rank test and multivariate StepAIC were applied to identify prognostic factors. The median age was 30 years (range 17-66). Tumors were located in the cerebral/cerebellar hemispheres, midline structures and cerebello-pontine angle in 53%, 38% and 9%. MGMT promoter methylation was present in eight patients (14%). GTR (39/58 patients) significantly reduced the likelihood of tumor recurrence (p = 0.0001). Tumor relapse occurred in 16 patients (28%) after a median progression-free survival (PFS) of 135 months (range 6-153 months); there was one tumor-related death. PFS at 5 and 10 years was 67% and 53%. In multivariate analysis, PFS was significantly prolonged in patients with GTR (HR 0.1; CI 0.03-0.37; p < 0.001), unmethylated MGMT promoter (HR 0.18; CI 0.05-0.64; p = 0.009) and midline tumors (HR 0.21; CI 0.06-0.78; p = 0.02). In conclusion, MGMT promoter methylation status and tumor location were identified as novel prognostic factors in adult PAs, pointing at distinct molecular subtypes and detecting patients in need of close observance and intensified treatment.

Recent studies suggest that glioblastomas (GBMs) contacting the subventricular zone (SVZ) as the main adult neurogenic niche confer a dismal prognosis but disregard the unique molecular and prognostic phenotype associated with isocitrate dehydrogenase 1 (IDH1) mutations. We therefore examined location-dependent prognostic factors, growth, and recurrence patterns in a consecutive cohort of 285 IDH1-wildtype GBMs. Based on pre-operative contrast-enhanced MRI, patients were allotted to four location-dependent groups with (SVZ+; groups I, II) and without (SVZ-; groups III, IV) SVZ involvement or with (cortex+; groups I, III) and without (cortex-; groups II, IV) cortical involvement and compared for demographic, treatment, imaging, and survival data at first diagnosis and recurrence. SVZ involvement was associated with lower Karnofsky performance score (p < 0.001), lower frequency of complete resections at first diagnosis (p < 0.0001), and lower non-surgical treatment intensity at recurrence (p < 0.001). Multivariate survival analysis employing a Cox proportional hazards model identified SVZ involvement as an independent prognosticator of inferior overall survival (p < 0.001) and survival after relapse (p = 0.041). In contrast, multifocal growth at first diagnosis (p = 0.031) and recurrence (p < 0.001), as well as distant recurrences (p < 0.0001), was more frequent in cortex+ GBMs. These findings offer the prospect for location-tailored prognostication and treatment based on factors assessable on pre-operative MRI.

Kinesins play an important role in many physiological functions including intracellular vesicle transport and mitosis. The emerging role of kinesins in different cancers led us to investigate the expression and functional role of kinesins in meningioma. Therefore, we re-analyzed our previous microarray dataset of benign, atypical, and anaplastic meningiomas (n = 62) and got evidence for differential expression of five kinesins (KIFC1, KIF4A, KIF11, KIF14 and KIF20A). Further validation in an extended study sample (n = 208) revealed a significant upregulation of these genes in WHO°I to °III meningiomas (WHO°I n = 61, WHO°II n = 88, and WHO°III n = 59), which was most pronounced in clinically more aggressive tumors of the same WHO grade. Immunohistochemical staining confirmed a WHO grade-associated upregulated protein expression in meningioma tissues. Furthermore, high mRNA expression levels of KIFC1, KIF11, KIF14 and KIF20A were associated with shorter progression-free survival. On a functional level, knockdown of kinesins in Ben-Men-1 cells and in the newly established anaplastic meningioma cell line NCH93 resulted in a significantly inhibited tumor cell proliferation upon siRNA-mediated downregulation of KIF11 in both cell lines by up to 95% and 71%, respectively. Taken together, in this study we were able to identify the prognostic and functional role of several kinesin family members of which KIF11 exhibits the most promising properties as a novel prognostic marker and therapeutic target, which may offer new treatment options for aggressive meningiomas.

Medulloblastoma is the most common malignant brain tumor in children and represents 20% of all pediatric central nervous system neoplasms. While advances in surgery, radiation and chemotherapy have improved overall survival, the lifelong sequelae of these treatments represent a major health care burden and have led to ongoing efforts to find effective targeted treatments. There is a well-recognized male bias in medulloblastoma diagnosis, although the mechanism remains unknown. Herein, we identify a sex-specific role for the transcription factor Signal Transducer and Activator of Transcription 3 (STAT3) in the Sonic Hedgehog (SHH) medulloblastoma subgroup. Specific deletion of Stat3 from granule cell precursors in a spontaneous mouse model of SHH medulloblastoma completely protects male, but not female mice from tumor initiation. Segregation of SHH medulloblastoma patients into high and low STAT3 expressing cohorts shows that low STAT3 expression correlates with improved overall survival in male patients. We observe sex specific changes in IL-10 and IL-6 expression and show that IL-6 stimulation enhances SHH-mediated gene transcription in a STAT3-dependent manner. Together these data identify STAT3 as a key molecule underpinning the sexual dimorphism in medulloblastoma.

The impact of protein-coding genes on cancer onset and progression is a well-established paradigm in molecular oncology. Nevertheless, unveiling the contribution of the noncoding genes-including long noncoding RNAs (lncRNAs)-to tumorigenesis represents a great challenge for personalized medicine, since they (i) constitute the majority of the human genome, (ii) are essential and flexible regulators of gene expression and (iii) present all types of genomic alterations described for protein-coding genes. LncRNAs have been increasingly associated with cancer, their highly tissue- and cancer type-specific expression making them attractive candidates as both biomarkers and therapeutic targets. Medulloblastoma is one of the most common malignant pediatric brain tumors. Group 3 is the most aggressive subgroup, showing the highest rate of metastasis at diagnosis. Transcriptomics and reverse genetics approaches were combined to identify lncRNAs implicated in Group 3 Medulloblastoma biology. Here we present the first collection of lncRNAs dependent on the activity of the MYC oncogene, the major driver gene of Group 3 Medulloblastoma. We assessed the expression profile of selected lncRNAs in Group 3 primary tumors and functionally characterized these species. Overall, our data demonstrate the direct involvement of three lncRNAs in Medulloblastoma cancer cell phenotypes.

The survivin suppressant YM155 is a drug candidate for neuroblastoma. Here, we tested YM155 in 101 neuroblastoma cell lines (19 parental cell lines, 82 drug-adapted sublines). Seventy seven (77) cell lines displayed YM155 IC50s in the range of clinical YM155 concentrations. ABCB1 was an important determinant of YM155 resistance. The activity of the ABCB1 inhibitor zosuquidar ranged from being similar to that of the structurally different ABCB1 inhibitor verapamil to being 65-fold higher. ABCB1 sequence variations may be responsible for this, suggesting that the design of variant-specific ABCB1 inhibitors may be possible. Further, we showed that ABCC1 confers YM155 resistance. Previously, p53 depletion had resulted in decreased YM155 sensitivity. However, TP53-mutant cells were not generally less sensitive to YM155 than TP53 wild-type cells in this study. Finally, YM155 cross-resistance profiles differed between cells adapted to drugs as similar as cisplatin and carboplatin. In conclusion, the large cell line panel was necessary to reveal an unanticipated complexity of the YM155 response in neuroblastoma cell lines with acquired drug resistance. Novel findings include that ABCC1 mediates YM155 resistance and that YM155 cross-resistance profiles differ between cell lines adapted to drugs as similar as cisplatin and carboplatin.