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Oncogenic FGFR3–TACC3 gene fusions signal through phosphorylated PIN4 to trigger biogenesis of peroxisomes and synthesis of new proteins, enabling mitochondrial respiration and tumour growth. Fusion gene stimulates tumour metabolism FGFR3 - TACC3 gene fusions are oncogenic and have been found in many cancer types, but how they drive tumour growth is unknown. Antonio Iavarone and colleagues show that the fusion protein activates mitochondrial metabolism, which promotes protein synthesis and thereby stimulates tumour growth. The team suggest that this reliance on mitochondrial respiration could open up a new therapeutic route for treating tumours that carry the FGFR3 - TACC3 fusion gene. Chromosomal translocations that generate in-frame oncogenic gene fusions are notable examples of the success of targeted cancer therapies 1 , 2 , 3 . We have previously described gene fusions of FGFR3 - TACC3 (F3–T3) in 3% of human glioblastoma cases 4 . Subsequent studies have reported similar frequencies of F3–T3 in many other cancers, indicating that F3–T3 is a commonly occuring fusion across all tumour types 5 , 6 . F3–T3 fusions are potent oncogenes that confer sensitivity to FGFR inhibitors, but the downstream oncogenic signalling pathways remain unknown 2 , 4 , 5 , 6 . Here we show that human tumours with F3–T3 fusions cluster within transcriptional subgroups that are characterized by the activation of mitochondrial functions. F3–T3 activates oxidative phosphorylation and mitochondrial biogenesis and induces sensitivity to inhibitors of oxidative metabolism. Phosphorylation of the phosphopeptide PIN4 is an intermediate step in the signalling pathway of the activation of mitochondrial metabolism. The F3–T3–PIN4 axis triggers the biogenesis of peroxisomes and the synthesis of new proteins. The anabolic response converges on the PGC1α coactivator through the production of intracellular reactive oxygen species, which enables mitochondrial respiration and tumour growth. These data illustrate the oncogenic circuit engaged by F3–T3 and show that F3–T3-positive tumours rely on mitochondrial respiration, highlighting this pathway as a therapeutic opportunity for the treatment of tumours with F3–T3 fusions. We also provide insights into the genetic alterations that initiate the chain of metabolic responses that drive mitochondrial metabolism in cancer.

Key Points O 6 -methylguanine-DNA methyltransferase ( MGMT ) promoter methylation predicts responsiveness to alkylating chemotherapies in glioblastoma, but is not a prognostic biomarker in gliomas lacking isocitrate dehydrogenase gene mutations Treatment decisions in elderly patients with glioblastoma should take MGMT promoter methylation status into account MGMT testing to select patients with glioblastoma for clinical trials is feasible, and withholding temozolomide from patients without MGMT promoter methylation is justified in this context MGMT -mediated resistance to alkylating chemotherapy is not overcome by alternative dosing schedules, but might be circumvented by the use of alternative treatments Epigenetic inactivation of MGMT might facilitate the induction of point mutations in TP53 and other oncogenes during tumorigenesis and tumour progression Quality-assured MGMT testing should be implemented as a molecular diagnostic method in the next WHO classification of brain tumours The DNA repair protein O 6 -methylguanine-DNA methyltransferase (MGMT) might interfere with alkylating agent chemotherapy in patients with glioma or glioblastoma. In this Review, Wick and colleagues discuss how epigenetic silencing of the MGMT gene via promotor methylation is associated with improved response to chemotherapy, and with improved survival, in patients with glioblastoma and other gliomas. The authors also highlight the usefulness of MGMT promotor methylation as a biomarker for both clinical practice and the design of treatment trials. Many patients with malignant gliomas do not respond to alkylating agent chemotherapy. Alkylator resistance of glioma cells is mainly mediated by the DNA repair enzyme O 6 -methylguanine-DNA methyltransferase (MGMT). Epigenetic silencing of the MGMT gene by promoter methylation in glioma cells compromises this DNA repair mechanism and increases chemosensitivity. MGMT promoter methylation is, therefore, a strong prognostic biomarker in paediatric and adult patients with glioblastoma treated with temozolomide. Notably, elderly patients (>65–70 years) with glioblastoma whose tumours lack MGMT promoter methylation derive minimal benefit from such chemotherapy. Thus, MGMT promoter methylation status has become a frequently requested laboratory test in neuro-oncology. This Review presents current data on the prognostic and predictive relevance of MGMT testing, discusses clinical trials that have used MGMT status to select participants, evaluates known issues concerning the molecular testing procedure, and addresses the necessity for molecular-context-dependent interpretation of MGMT test results. Whether MGMT promoter methylation testing should be offered to all individuals with glioblastoma, or only to elderly patients and those in clinical trials, is also discussed. Justifications for withholding alkylating agent chemotherapy in patients with MGMT -unmethylated glioblastomas outside clinical trials, and the potential role for MGMT testing in other gliomas, are also discussed.

Abstract Glioblastoma (GBM) is the most common primary malignant brain tumor in adults, yet it remains refractory to systemic therapy. Elimination of senescent cells has emerged as a promising new treatment approach against cancer. Here, we investigated the contribution of senescent cells to GBM progression. Senescent cells are identified in patient and mouse GBMs. Partial removal of p16 Ink4a -expressing malignant senescent cells, which make up less than 7 % of the tumor, modifies the tumor ecosystem and improves the survival of GBM-bearing female mice. By combining single cell and bulk RNA sequencing, immunohistochemistry and genetic knockdowns, we identify the NRF2 transcription factor as a determinant of the senescent phenotype. Remarkably, our mouse senescent transcriptional signature and underlying mechanisms of senescence are conserved in patient GBMs, in whom higher senescence scores correlate with shorter survival times. These findings suggest that senolytic drug therapy may be a beneficial adjuvant therapy for patients with GBM.

Introduction Glioblastoma (GBM) is the most common and aggressive primary brain cancer in adults. Few cytotoxic chemotherapies have been shown to be effective against GBM, due in part to the presence of the blood–brain barrier (BBB), which reduces the penetration of chemotherapies from the blood to the brain. Ultrasound-induced BBB opening (US-BBB) has been shown to increase the penetration of multiple chemotherapeutic agents in the brain in animal models. In the current study, the anti-tumor activity of carboplatin chemotherapy with and without US-BBB was investigated in several GBM mouse models. Methods First, the IC50 of two commercial (U87 and U251) and six patient-derived GBM cell lines (PDCL) to carboplatin was measured. Next, U87 was subcutaneously grafted to a nude mouse model to test the in vivo response of the tumor to carboplatin in the absence of the BBB. Lastly, nude mice bearing orthotopically xenografted GBM cell lines (U87 or a PDCL) were randomized to four experimental groups: (i) untreated, (ii) US-BBB alone, (iii) carboplatin alone and, (iv) carboplatin + US-BBB. Mice were treated once weekly for 4 weeks and monitored for toxicity, tumor growth, and survival. Results Carboplatin plus US-BBB enhanced survival (p = 0.03) and delayed tumor growth (p < 0.05) of GBM-bearing mice compared to carboplatin alone, with a 4.2-fold increase of carboplatin penetration in the brain, without evidence of significant neurological or systemic toxicity. Conclusions Carboplatin efficacy was enhanced in GBM mouse models with US-BBB and appears to be a promising chemotherapy for this approach.

Chordoid glioma (ChG) is a characteristic, slow growing, and well-circumscribed diencephalic tumor, whose mutational landscape is unknown. Here we report the analysis of 16 ChG by whole-exome and RNA-sequencing. We found that 15 ChG harbor the same PRKCA D463H mutation. PRKCA encodes the Protein kinase C (PKC) isozyme alpha (PKCα) and is mutated in a wide range of human cancers. However the hot spot PRKCA D463H mutation was not described in other tumors. PRKC A D463H is strongly associated with the activation of protein translation initiation (EIF2) pathway. PKCα D463H mRNA levels are more abundant than wild-type PKCα transcripts, while PKCα D463H is less stable than the PCKα WT protein. Compared to PCKα WT , the PKCα D463H protein is depleted from the cell membrane. The PKCα D463H mutant enhances proliferation of astrocytes and tanycytes, the cells of origin of ChG. In conclusion, our study identifies the hallmark mutation for chordoid gliomas and provides mechanistic insights on ChG oncogenesis. Chordoid glioma is a slow growing diencephalic tumor whose mutational landscape is poorly characterized. Here, the authors perform whole-exome and RNA-sequencing and find that 15 of 16 chordoid glioma cases studied harbor the same PRKCA mutation which results in enhanced proliferation.

Previous genome-wide association studies (GWASs) have shown that common genetic variation contributes to the heritable risk of glioma. To identify new glioma susceptibility loci, we conducted a meta-analysis of four GWAS (totalling 4,147 cases and 7,435 controls), with imputation using 1000 Genomes and UK10K Project data as reference. After genotyping an additional 1,490 cases and 1,723 controls we identify new risk loci for glioblastoma (GBM) at 12q23.33 (rs3851634, near POLR3B , P =3.02 × 10 −9 ) and non-GBM at 10q25.2 (rs11196067, near VTI1A , P =4.32 × 10 −8 ), 11q23.2 (rs648044, near ZBTB16 , P =6.26 × 10 −11 ), 12q21.2 (rs12230172, P =7.53 × 10 −11 ) and 15q24.2 (rs1801591, near ETFA , P =5.71 × 10 −9 ). Our findings provide further insights into the genetic basis of the different glioma subtypes. Using meta-analysis of previous genome-wide association studies against the latest reference variant databases, this work identifies five new risk loci for glioblastoma and non-glioblastoma type of glioma.

The 2016 WHO classification of Tumors of the Central Nervous System brought major conceptual and practical changes in the classification of diffuse gliomas, by combining molecular features and histology into ‘integrated’ diagnoses. In diffuse gliomas, molecular profiling has thus become essential for nosological purposes, as well as to plan adequate treatment strategies and identify patients susceptible of target therapy. WHO grade II (low grade) and grade III (anaplastic) diffuse gliomas form a heterogeneous group of neoplasms, also known as ‘lower-grade gliomas’, characterized by a wide range of malignant potential. Molecular profile accounts for this biological diversity, and provides an accurate prognostic stratification of tumors in this group. Treatment strategies in lower-grade gliomas are ultimately based on molecular profile and WHO grade, as well as on patient characteristics such as age and Karnofsky performance status. The purpose of this review is to summarize recent advances in the classification of grade II and III gliomas, synthesize current treatment schemes according to molecular profile and describe ongoing research and future perspectives for the use of target therapies.

The incidence and risk factors associated with radiation-induced leukoencephalopathy (RIL) in long-term survivors of high-grade glioma (HGG) are still poorly investigated. We performed a retrospective research in our institutional database for patients with supratentorial HGG treated with focal radiotherapy, having a progression-free overall survival > 30 months and available germline DNA. We reviewed MRI scans for signs of leukoencephalopathy on T2/FLAIR sequences, and medical records for information on cerebrovascular risk factors and neurological symptoms. We investigated a panel of candidate single nucleotide polymorphisms (SNPs) to assess genetic risk. Eighty-one HGG patients (18 grade IV and 63 grade III, 50M/31F) were included in the study. The median age at the time of radiotherapy was 48 years old (range 18–69). The median follow-up after the completion of radiotherapy was 79 months. A total of 44 patients (44/81, 54.3%) developed RIL during follow-up. Twenty-nine of the 44 patients developed consistent symptoms such as subcortical dementia (n = 28), gait disturbances (n = 12), and urinary incontinence (n = 9). The cumulative incidence of RIL was 21% at 12 months, 42% at 36 months, and 48% at 60 months. Age > 60 years, smoking, and the germline SNP rs2120825 (PPARg locus) were associated with an increased risk of RIL. Our study identified potential risk factors for the development of RIL (age, smoking, and the germline SNP rs2120825) and established the rationale for testing PPARg agonists in the prevention and management of late-delayed radiation-induced neurotoxicity.

Loss of ATRX function, a diagnostic criterion of IDH-mutant astrocytoma, is closely associated with alternative lengthening of telomeres (ALT), a telomere maintenance mechanism (TMM). As immunohistochemical (IHC) assessment of ATRX is error-prone, sequencing has been integrated into clinical workflows. While frameshift and nonsense variants can be classified as loss-of-function (LOF) mutations, missense variants remain difficult to interpret. To address this, we analyzed ATRX -altered gliomas from TCGA (N = 539 tumors, 587 alterations) and a local cohort of 100 diffuse gliomas. Aside from IDH-mutant astrocytoma and H3.3-mutant glioma, glioblastoma (13–19%), oligodendroglioma (2%), and MAPK-altered tumors (2–7%) were consistently represented in both cohorts. Missense mutations accounted for 18% (TCGA) and 28% (local) of variants. Functional annotation of TCGA missense mutations using IHC, NGS-based TMM status, transcript levels, and RNA-seq–derived telomerase signatures (EXTEND) allowed us to functionally annotate only 3 of 106 variants. Therefore, we directly assessed the TMM status in the local cohort, using the TeloDIAG assay and retrieved 80% of ALT-positive samples, corresponding to 96% (N = 53) of IDH-mutant astrocytomas and 74% (N = 19) of histone-mutant gliomas, as expected. Importantly, ALT activity was also observed in 42% (N = 19) of glioblastomas and 86% (N = 7) of MAPK-altered gliomas, indicating potential implications for clinical behavior and therapeutic targeting. While sensitivity for LOF variant detection was similar—88% for TMM and 80% for IHC—TMM performed better for missense alterations (85 vs. 65%) and is more discriminant in overall survival prediction. Overall, 83% (N = 24) of missense mutations associated with an ALT phenotype were located within the major functional domains of the ATRX protein, compared to only 59% when considering all missense mutations, highlighting the functional relevance of the assay. Collectively, these findings emphasize the clinical value of functional TMM assessment in refining glioma diagnosis. Last, targeting of ALT-associated DNA-damage deficiency and immunogenic context is under clinical investigation, highlighting the promising theranostic potential of TMM assessment.

Background The Follicle Stimulating Hormone receptor (FSHR) is expressed by the vascular endothelium in a wide range of human tumors. It was not determined however if FSHR is present in metastases which are responsible for the terminal illness. Methods We used immunohistochemistry based on a highly FSHR-specific monoclonal antibody to detect FSHR in cancer metastases from 6 major tumor types (lung, breast, prostate, colon, kidney, and leiomyosarcoma ) to 6 frequent locations (bone, liver, lymph node, brain, lung, and pleura) of 209 patients. Results In 166 patients examined (79%), FSHR was expressed by blood vessels associated with metastatic tissue. FSHR-positive vessels were present in the interior of the tumors and some few millimeters outside, in the normally appearing tissue. In the interior of the metastases, the density of the FSHR-positive vessels was constant up to 7 mm, the maximum depth available in the analyzed sections. No significant differences were noticed between the density of FSHR-positive vessels inside vs. outside tumors for metastases from lung, breast, colon, and kidney cancers. In contrast, for prostate cancer metastases, the density of FSHR-positive vessels was about 3-fold higher at the exterior of the tumor compared to the interior. Among brain metastases, the density of FSHR-positive vessels was highest in lung and kidney cancer, and lowest in prostate and colon cancer. In metastases of breast cancer to the lung pleura, the percentage of blood vessels expressing FSHR was positively correlated with the progesterone receptor level, but not with either HER-2 or estrogen receptors. In normal tissues corresponding to the host organs for the analyzed metastases, obtained from patients not known to have cancer, FSHR staining was absent, with the exception of approx. 1% of the vessels in non tumoral temporal lobe epilepsy samples. Conclusion FSHR is expressed by the endothelium of blood vessels in the majority of metastatic tumors.