Region-specific DNA hydroxymethylation along the malignant progression of IDH-mutant gliomas.

The majority of low-grade isocitrate dehydrogenase-mutant (IDHmt) gliomas undergo malignant progression (MP), but their underlying mechanism remains unclear. IDHmt gliomas exhibit global DNA methylation, and our previous report suggested that MP could be partly attributed to passive demethylation caused by accelerated cell cycles. However, during MP, there is also active demethylation mediated by ten-eleven translocation, such as DNA hydroxymethylation. Hydroxymethylation is reported to potentially contribute to gene expression regulation, but its role in MP remains under investigation. Therefore, we conducted a comprehensive analysis of hydroxymethylation during MP of IDHmt astrocytoma. Five primary/malignantly progressed IDHmt astrocytoma pairs were analyzed with oxidative bisulfite and the Infinium EPIC methylation array, detecting 5-hydroxymethyl cytosine at over 850,000 locations for region-specific hydroxymethylation assessment. Notably, we observed significant sharing of hydroxymethylated genomic regions during MP across the samples. Hydroxymethylated CpGs were enriched in open sea and intergenic regions (p < 0.001), and genes undergoing hydroxymethylation were significantly associated with cancer-related signaling pathways. RNA sequencing data integration identified 91 genes with significant positive/negative hydroxymethylation-expression correlations. Functional analysis suggested that positively correlated genes are involved in cell-cycle promotion, while negatively correlated ones are associated with antineoplastic functions. Analyses of The Cancer Genome Atlas clinical data on glioma were in line with these findings. Motif-enrichment analysis suggested the potential involvement of the transcription factor KLF4 in hydroxymethylation-based gene regulation. Our findings shed light on the significance of region-specific DNA hydroxymethylation in glioma MP and suggest its potential role in cancer-related gene expression and IDHmt glioma malignancy.

Transcriptomic and epigenetic dissection of spinal ependymoma (SP-EPN) identifies clinically relevant subtypes enriched for tumors with and without NF2 mutation.

Ependymomas encompass multiple clinically relevant tumor types based on localization and molecular profiles. Tumors of the methylation class "spinal ependymoma" (SP-EPN) represent the most common intramedullary neoplasms in children and adults. However, their developmental origin is ill-defined, molecular data are scarce, and the potential heterogeneity within SP-EPN remains unexplored. The only known recurrent genetic events in SP-EPN are loss of chromosome 22q and NF2 mutations, but neither types and frequency of these alterations nor their clinical relevance have been described in a large, epigenetically defined series. Transcriptomic (n = 72), epigenetic (n = 225), genetic (n = 134), and clinical data (n = 112) were integrated for a detailed molecular overview on SP-EPN. Additionally, we mapped SP-EPN transcriptomes to developmental atlases of the developing and adult spinal cord to uncover potential developmental origins of these tumors. The integration of transcriptomic ependymoma data with single-cell atlases of the spinal cord revealed that SP-EPN display the highest similarities to mature adult ependymal cells. Unsupervised hierarchical clustering of transcriptomic data together with integrated analysis of methylation profiles identified two molecular SP-EPN subtypes. Subtype A tumors primarily carried previously known germline or sporadic NF2 mutations together with 22q loss (bi-allelic NF2 loss), resulting in decreased NF2 expression. Furthermore, they more often presented as multilocular disease and demonstrated a significantly reduced progression-free survival as compared to SP-EP subtype B. In contrast, subtype B predominantly contained samples without NF2 mutation detected in sequencing together with 22q loss (monoallelic NF2 loss). These tumors showed regular NF2 expression but more extensive global copy number alterations. Based on integrated molecular profiling of a large multi-center cohort, we identified two distinct SP-EPN subtypes with important implications for genetic counseling, patient surveillance, and drug development priorities.

Diffuse peritoneal dissemination of intracranial pure germinoma via ventriculoperitoneal shunt.

Germinomas frequently cause hydrocephalus, and ventriculoperitoneal shunts (VPS) have been commonly used for their management. Although VPS can potentially serve as a route for peritoneal dissemination of germinomas, the abdominal imaging characteristics of this rare yet important complication remain unknown. In this article, we report the computed tomography imaging findings of diffuse peritoneal dissemination of intracranial germinoma.

CHD5 gene variant predicts leptomeningeal metastasis after surgical resection of brain metastases of breast cancer.

PURPOSE: Leptomeningeal metastasis (LM) is a complication of surgery for brain metastasis and is a risk factor of poor prognosis. The risk of LM is particularly high after surgery for a breast cancer metastasis to the brain. If the risk of LM after surgical resection for a brain metastasis were predictable, appropriate adjuvant therapy could be administered to individual patients to improve their prognosis. The present study aimed to reveal the genetic characteristics of brain metastases as means of predicting LM in breast cancer patients. METHODS: Ten patients with brain metastases of breast cancer presented LM after surgical resection were analyzed by whole-exome sequencing. RESULTS: A chromodomain-helicase-DNA-binding protein 5 (CHD5) gene alteration was detected in nine cases (90%), including a nonsynonymous variant in four cases and copy number deletion in five cases. CHD5 protein expression was lost in nine cases and had decreased in one case. The frequency of CHD5 gene alteration in brain metastases with LM was significantly higher than in primary breast cancer (2.3%) or in brain metastases of breast cancer (0%) (p < 0.0001). CONCLUSIONS: These results suggested that the CHD5 gene alteration was associated with LM after surgical resection of breast cancer brain metastases. Searching for the gene alteration might predict the LM risk after surgical resection.

PTPN11 variant may be a prognostic indicator of IDH-wildtype glioblastoma in a comprehensive genomic profiling cohort.

PURPOSE: Glioblastoma (GBM) is the most common type of primary malignant brain tumor and has a poor prognosis. Identifying novel targets and stratification strategies is urgently needed to improve patient survival. The present study aimed to identify clinically relevant genomic alterations in IDH-wildtype GBM using data from comprehensive genomic profiling (CGP) assays performed nationwide in Japan. METHODS: The CGP assay results of 392 IDH-wildtype GBM cases performed between October 2019 and February 2023 obtained from the Center for Cancer Genomics and Advanced Therapeutics were retrospectively analyzed. RESULTS: The median patient age was 52.5 years, and 207 patients (53%) were male. In the 286 patients for whom survival information was available, a protein-tyrosine phosphatase non-receptor type 11 (PTPN11) variant detected in 20 patients (6.8%) was extracted as the gene associated with significantly shorter overall survival (p = 0.002). Multivariate analysis demonstrated that the PTPN11 variant and poor performance status were independent prognostic indicators. In contrast, no prognostic impact was observed in the cohort in The Cancer Genome Atlas data. The discrepancy in the prognostic impact of the PTPN11 variant from these two pools might have resulted from differences in the biases affecting the survival of patients who underwent a CGP assay, including left-truncation and right-censored bias. However, survival simulation done to adjust for these biases showed that the prognostic impact of the PTPN11 variant was also significant. CONCLUSIONS: The PTPN11 variant was a negative prognostic indicator of IDH-wildtype GBM in the patient cohort with the CGP assay.

Lymphoproliferative disorder during temozolomide therapy; a representative case of a formidable complication and management challenges.

BACKGROUND: Lymphoproliferative disorder represents a heterogeneous clinicopathological spectrum characterized by uncontrolled proliferation of lymphocytes. Immunodeficiency is a major trigger of its development. While induction of immunodeficiency is a well-known adverse effect of temozolomide therapy, development of lymphoproliferative disorder following temozolomide therapy has not previously been described. CASE PRESENTATION: A patient with brainstem glioma developed constitutional symptoms, pancytopenia, splenomegaly and generalized lymphadenopathy during the 2nd cycle of maintenance therapy following induction therapy with temozolomide. Epstein-Barr virus-infected lymphocytes were observed histopathologically and "other iatrogenic immunodeficiency-associated lymphoproliferative disorder" (OIIA-LPD) was diagnosed. Although discontinuation of temozolomide led to rapid remission, relapse was observed 4 months later. CHOP chemotherapy was induced, resulting in secondary remission. Vigilant follow-up for another 14 months showed radiologically stable brainstem glioma and no further recurrence of OIIA-LPD. CONCLUSIONS: This is the first report documenting OIIA-LPD during temozolomide administration. Timely diagnosis of the disease and discontinuation of the causative agent were considered to be the management of choice. Close monitoring for relapse should be continued. Finding a balance between glioma management and controlling the remission of OIIA-LPD remains to be clarified.

Embryonal tumor with multilayered rosettes arising from the internal auditory canal of an adult: Illustrative case with molecular investigations.

Embryonal tumors with multilayered rosettes (ETMRs) are aggressive central nervous system (CNS) tumors that usually occur in young children. Here, we describe the first incidence of ETMR in an adult patient that also originated in the novel location of the internal auditory canal (IAC). The 36-year-old patient initially presented with unsteadiness, diplopia, and tinnitus. The tumor in the IAC was discovered on brain magnetic resonance imaging, and gross total resection was performed followed by pathological and molecular diagnosis. The patient received whole brain and spinal cord radiotherapy after an intracranial recurrence and adjuvant chemotherapy consisting of four cycles of ifosfamide, cisplatin, and etoposide. Progression was rapid; however, the patient survived for 22 months after diagnosis before succumbing to the disease. Molecular investigation revealed a DICER1 mutation at exon 25, and methylation classification categorized the tumor as ETMR, non-C19MC-altered. This case underscores the diverse possible presentations of ETMR, DICER1-mutated and the importance of molecular techniques to characterize and promptly treat atypical ETMR.

Indocyanine green illuminates the way to cut the tentorium in occipital transtentorial approach: technical note.

BACKGROUND AND IMPORTANCE: The occipital transtentorial approach is used to address lesions at the posterior incisural space or upper cerebellum. This approach is rarely used, making standardization of the surgical procedure challenging. Here we describe the effectiveness of indocyanine green (ICG) and dye markings before tentorial incision in charting a safe and bloodless surgical trajectory for improved manoeuvrability. CLINICAL PRESENTATION: The first case was a 40-year-old man with a residual pineal mass after chemoradiation therapy for pathologically-proven germinoma. Surgical resection was performed via left occipital craniotomy. Incision of the left cerebellar tentorium by a radiofrequency knife was preceded by visualization of the straight sinus and venous lake, which were marked with dye, enabling safe entry into the quadrigeminal cistern. Finally, total-resection of the mature teratoma was achieved. The second case was a 50-year-old man with an enhancing mass at the cerebellar vermis and left hemisphere. Left occipital craniotomy was followed by ICG administration, illuminating the straight sinus and a complex structure of dural venous channels, which were marked with dye. This visualization maximized the tentorial incision by carefully avoiding venous structures and widely exposed the upper cerebellum. Subtotal-resection of the tumor was achieved, with a diagnosis of glioblastoma. CONCLUSION: ICG administration and dye marking are feasible and useful methods for precise identification/visualization of venous structures. They enable maximization as well as safe and appropriate tentorial incision to provide a sufficient surgical corridor for the occipital transtentorial approach.

[Molecular Characteristics and Clinical Significance of Germ Cell Tumors].

Germ cell tumors(GCT), which predominantly emerge in the early to middle teenage years among males, affect the pineal gland, followed by the neurohypophysis, often presenting with site-specific symptoms. Diagnosis hinges on imaging, tumor markers(HCG and AFP), and pathological evaluation. The radiation dose/coverage and chemotherapy intensity are tailored to the distinction between the germinoma and non-germinoma types. Surgical resection is reserved for residual non-germinomas. Biological investigations have revealed frequent mutations in the RAS, MAPK, and PI3K pathways, with no obvious structural variations. These mutations are more prevalent in germinomas than in non-germinomas. Germinomas exhibit a strikingly low methylation status across the genome, mirroring the state of primordial germ cells(PGC), deemed as the cells of origin. Mitosis/meiosis-related genes are highly expressed in germinoma, which is another supporting evidence of PGCs as cells of origin. In contrast, non-germinomas display transcriptomic features that differentiate them into tissue formation and organogenesis. Frequent copy number alterations are another hallmark of GCTs. Among these, 12p gain has been identified as a negative prognostic factor in non-germinomas. Pathologically confirmed tumor cell content serves as a poor prognostic indicator in germinomas and requires external validation as a reliable marker. Given the significant long-term sequelae stemming from treatment burdens in vulnerable young patients, a need for targeted therapy has arisen. Ongoing genomic studies are exploring the pathogenesis and uncovering potential leads for the establishment of precision medicine.

Presentation, imaging, patterns of care, growth, and outcome in sporadic and von Hippel-Lindau-associated central nervous system hemangioblastomas.

OBJECT: Hemangioblastoma is a relatively rare neoplasm occurring mostly in the cerebellum that may arise sporadically or in the context of von Hippel-Lindau (VHL) syndrome. Presentation, imaging, natural history, surgical patterns of care, and outcomes are incompletely defined for this uncommon lesion. We reviewed our large institutional series to help clarify these issues. METHODS: Retrospective analysis of consecutive, neurosurgically managed CNS hemangioblastomas at Mayo Clinic, 1988-2018. RESULTS: Two hundred and eighty five hemangioblastomas were treated in 184 unique patients (115 sporadic, 69 VHL). Compared to sporadic patients, VHL patients were younger (36.7 vs 51.7 years; p < 0.0001), were treated while asymptomatic more commonly (47.3 vs 4.2%; p < 0.0001), had smaller lesions (6.6 vs 13.9 mL; p < 0.0001), and harbored lesions with associated cysts less frequently (51.0 vs 75.0%; p = 0.0002). Macrocystic tumor architecture was associated with larger lesion size and greater symptom severity. Solid lesions later formed cysts at a median 130 months. Growth in both total volume and solid component accelerated after cyst formation (10.6 and 6.0 times median rate prior to cyst emergence). VHL patients died at a younger age (47.9 vs 74.5, p = 0.0017) and were more likely to die of direct disease sequelae. Though treatment-free survival time was significantly longer in sporadic cases, a substantial fraction (> 40%) developed tumor recurrence/progression requiring additional treatment. CONCLUSIONS: Hemangioblastoma presentation varies with etiology and clinical course is more complicated in VHL cases. Nodular lesions often develop cysts over time which is associated with accelerated tumor growth. Sporadic cases have a previously unappreciated but substantial risk of late recurrence/progression requiring treatment.

Revisitation of imaging features of skull base chondrosarcoma in comparison to chordoma.

PURPOSE: Pre-surgical diagnosis of skull base chondrosarcoma (SBC) is often challenging due to the resemblance to chordoma. The goal of this study was to develop an optimal method for predicting SBC diagnosis. METHODS: This retrospective study included patients with histologically diagnosed SBC and skull base chordoma. Their clinical and radiologic features were compared, and the predictive factors of SBC were examined. RESULTS: Forty-one patients with SBC and 41 with chordoma were included. Most SBCs exhibited hypointensity (25, 64.1%) or isointensity (12, 30.8%) on T1-weighted images, and hyperintensity (34, 87.1%) or mixed intensity (5, 12.8%) on T2-weighted images. MRI contrast enhancement was usually avid or fair (89.7%) with "arabesque"-like pattern (41.0%). The lateral/paramidline location was more common in SBC than in chordoma (85.4% vs. 9.8%; P < 0.01), while midline SBCs (14.6%) were also possible. Multivariate analysis demonstrated that higher apparent diffusion coefficient (ADC) value (unit odds ratio 1.01; 95% confidence interval 1.00-1.02; P < 0.01) was associated with an SBC diagnosis. An ADC value of ≥ 1750 × 10-6 mm2/s demonstrated a strong association with an SBC diagnosis (odds ratio 5.89 × 102; 95% confidence interval 51.0-6.80 × 103; P < 0.01) and yielded a sensitivity of 93.9%, specificity of 97.4%, positive predictive value of 96.9%, and negative predictive value of 95.0%. CONCLUSION: The ADC-based method is helpful in distinguishing SBC from chordoma and readily applicable in clinical practice. The prediction accuracy increases when other characteristics of SBC, such as non-midline location and arabesque-like enhancement, are considered together.

Advances in Molecular Profiling and Developing Clinical Trials of CNS Germ Cell Tumors: Present and Future Directions.

PURPOSE OF REVIEW: The last decade has seen significant improvements in the management and understanding of the pathogenesis of CNS germ cell tumors (GCTs) by studies on genomic and epigenomic analyses, and published results of clinical trials. This review highlights the new findings to stay up-to-date on the knowledge and better inform the future directions. RECENT FINDINGS: CNS GCTs are characterized by either MAPK or PI3K pathway mutations. Germinoma has a striking global hypo-methylation, analogous to its hypothesized cell-of-origin; primordial germ cell. Micro RNA cluster mir-371-373 and mir-302/367 are characteristic of GCTs, which have potential for liquid biopsy. Clinical trials have revealed whole-ventricular irradiation for germinoma and local radiotherapy for localized non-germinomatous GCTs seem to be sufficient for tumor control. Advancements in basic, translational, and clinical studies are improving our understanding of this rare disease. Further studies are needed, especially in the field of radiomics, liquid biopsy, genomic structural variants, and treatment stratification, to better structure the future management scheme.

[Evolving Exploration of the Pathogenesis of CNS Germ Cell Tumors with Regard to Precision Medicine].

Genomic and epigenomic analyses have progressed the exploration of the pathogenesis of CNS germ cell tumors(GCTs)in the past decade. GCTs are characterized by mutations in MAPK or PI3K pathways(55%)and unstable chromosomes, especially 12p gain(45%), as well as global hypomethylation in germinoma. Highly specific microRNA, miR-371a-3p, can be a diagnostic marker in serum and cerebrospinal fluid. Tumor cell content examined in H-E specimens has a prognostic value in germinoma: cases with higher tumor cell content show a worse prognosis. 12p gain in non-germinomatous GCTs(NGGCTs)has an unfavorable prognostic significance. PD-L1 and PD-1 are highly expressed in germinomas and the tumor cell microenvironment, respectively, highlighting the potential effectiveness of immune checkpoint inhibitors. Clinical trials from the Children's Oncology Group(COG)in the US and the Society for Paediatric Oncology(SIOP)in Europe and Japan have shown that whole ventricular irradiation is the most appropriate for germinomas, and that radiation fields can be reduced to the whole ventricle or a local area for localized NGGCTs. Toward personalized medicine, investigations into the structural abnormalities and variants in non-coding regions are needed to develop targeted therapy. A stratified treatment regimen is expected by incorporating newly-found biomarkers to reduce the treatment burden for generally young patients and circumvent late toxicity and sequelae. Establishing effective treatments is crucial for relapsed GCT that has a dismal prognosis.

[Hemangioblastoma and von Hippel-Lindau Disease].

Hemangioblastoma(HB)is a tumor that frequently occurs in von Hippel-Lindau(VHL)disease, a hereditary tumor disease. It is a benign tumor and excision is the first choice of treatment, but in VHL disease, where HB occurs frequently, the emergence of more promising molecularly-targeted therapeutic agents has been desired. In this paper, we first explain HB and VHL disease and then outline the function of the VHL gene and the mechanism of onset of VHL disease. After that, we explain the analysis technology and frequency of VHL gene abnormalities and finally describe HIF2α inhibitors, which are promising as molecularly-targeted therapeutic agents for VHL disease. As the medical system for personalized medicine/precision medicine is being developed in Japan, it is expected that HB and VHL diseases will attract attention as target diseases in the future.

[Molecularly Targeted Therapy for Craniopharyngioma].

Craniopharyngioma is a pathologically benign but clinically malignant brain tumor typically located in the parasellar region. It is treated by surgical resection, but in most cases, total removal is not amenable due to its adhesion to the adjacent vital structures, such as the optic nerve, hypothalamus, and pituitary stalk. Often, tumor regrowth or recurrence occursand it is usually treated with either re-resection or radiotherapy, including stereotactic radiosurgery. Either treatment carries some important risks, including blindness, hypopituitarism, and cognitive impairment. A recent comprehensive genomic analysis revealed that the majority of papillary craniopharyngioma cases harbor a hotspot BRAF-V600E mutation. Several case reports have illustrated dramatic response of the residual or recurrent papillary craniopharyngioma to molecularly targeted therapy with a BRAF inhibitor(vemurafenib or dabrafenib)and a MEK inhibitor(trametinib), which are currently approved for melanoma and non-small cell lung carcinoma. This medical treatment can potentially be a wonderful treatment option for papillary craniopharyngioma, given its freedom from the aforementioned serious risks associated with surgery and radiotherapy.

Histopathology and prognosis of germ cell tumors metastatic to brain: cohort study.

INTRODUCTION: Germ cell tumors (GCTs) are uncommon neoplasms predominantly arising in midline tissues. The prognostic significance of histopathology in predicting metastatic GCT behavior is poorly understood. METHODS: Multicenter international cohort study including 29 patients with GCTs metastatic to brain were retrospectively investigated (18 patients from Mayo Clinic and 11 patients from the intracranial germ cell tumor genome analysis consortium in Japan). Clinical characteristics were analyzed using the Chi-square test (two-tailed) for categorical variables and using the log-rank test for survival data. RESULTS: Median age at treatment was 31 years (range 14-58). Primary disease sites were testis (71%), mediastinum (18%), and female reproductive organs (11%). Median metastatic interval was 223 days (range, 6-6124). Median follow-up was 346 days (range, 1-5356), with 16 deaths (57%) occurring after the median overall survival of 455 days. Actuarial one-year survival was 51%; 12-of-16 deaths (75%) were attributed to intracranial disease. Appearance of the same GCT subtype at the metastatic site as the primary was high for non-seminomatous GCT (NSGCT, 64-100%), but low for seminoma/dysgerminoma and mature teratoma (MT, 14, 17%, respectively). Gain of a new component was seen in 4 (20%)-3 of which included embryonal carcinoma (EC) at the primary site (75%). Incidence of cases without seminoma/dysgerminoma increased significantly after metastasis (p = 0.02). Metastatic interval was shorter in cases with histological change (199 vs 454 days, p = 0.009). Overall survival was associated with MT primary histopathology (p = 0.02). CONCLUSION: Histological differentiation at the primary GCT site influences metastatic prognosis. Aggressive behavior is associated with NSGCT, while EC frequently demonstrates multi-directional histological differentiation after brain metastasis, and such histological dynamism is associated with shorter metastatic interval. Most metastases occurred within one year of diagnosis, emphasizing the need for close surveillance in newly diagnosed extra-cranial GCT.

[Comparison with Overseas Glioma Treatment: Significance of Clinical Practice Abroad].

While the medical equipment, treatment strategies, and drugs used for glioma patients are not much different among developed countries, leading to similar treatment outcomes, players involved in the management as well as the medical/social systems and environments differ greatly between Japan and North America. In North America, division of work is established and multiple departments consider patients as their "own," and are therefore deeply committed to the patients' care which makes the transition of care efficient and smooth for patients. The tumor board was one representative. Neurosurgeons can focus on surgery and clinics, and have dedicated research time allotted for weeks. Due to private insurance in the US, surgery is costly for patients. Religion is part of their life and influences the patients' attitudes toward and ways of thinking about disease, and sometimes unfavorable treatment results. Admittedly, there are advantages and disadvantages in both the Japanese medical environment and those around the world, but it is worthwhile to consider how patients outside of Japan are treated and look back at our practice. It would then widen our perspective and make us recognize that the commonalities are truth.

Awake craniotomies for epileptic gliomas: intraoperative and postoperative seizure control and prognostic factors.

PURPOSE: Awake craniotomy is well-established for tumors resected in eloquent brain areas. Whether awake craniotomy provides improved seizure control in patients with epileptic gliomas has not been well evaluated. This study analyzed the incidence, risk factors and outcome of seizures during and following awake craniotomies for patients presenting with epilepsy and glioma. METHODS: Forty-one patients undergoing awake craniotomies for epileptic gliomas were retrospectively analyzed. Postoperative seizure was defined as either early (postoperative day 7 + before) or late onset (after postoperative day 7). Neurologic function was assessed with modified Rankin Scales (mRS) and seizure outcome was assessed using International League Against Epilepsy (ILAE) classification. Multivariable logistic regression was used for clinical variables associated with postoperative seizures. RESULTS: Three patients (7.3%) had intraoperative seizures however did not fail the awake craniotomies. Mean mRS before and after the awake craniotomies were 2.4 and 2.1, respectively (P = 0.032). Fourteen (34.1%) patients had early seizures, which caused longer hospitalization than those without early seizures (P = 0.03). Surgical resection to isocitrate dehydrogenase 1 (IDH1) mutation tumors, comparing to IDH1 wild type tumors, caused better postoperative seizure control. 6-month late seizure freedom was achieved in 33 patients (80.5%). Early seizure recurrence (odds ratio = 30.75; P = 0.039) and postoperative mRS ≥ 3 (odds ratio = 7.00; P = 0.047) were independent risk factors for late seizures. CONCLUSIONS: Intraoperative seizures could be well-controlled during awake craniotomies. Early postoperative seizures extended hospitalization and strongly predicted late seizure recurrence. Awake craniotomies benefited long-term seizure control in patients with epileptic gliomas.

Genome-wide methylation profiles in primary intracranial germ cell tumors indicate a primordial germ cell origin for germinomas.

Intracranial germ cell tumors (iGCTs) are the second most common brain tumors among children under 14 in Japan. The World Health Organization classification recognizes several subtypes of iGCTs, which are conventionally subclassified into pure germinoma or non-germinomatous GCTs. Recent exhaustive genomic studies showed that mutations of the genes involved in the MAPK and/or PI3K pathways are common in iGCTs; however, the mechanisms of how different subtypes develop, often as a mixed-GCT, are unknown. To elucidate the pathogenesis of iGCTs, we investigated 61 GCTs of various subtypes by genome-wide DNA methylation profiling. We showed that pure germinomas are characterized by global low DNA methylation, a unique epigenetic feature making them distinct from all other iGCTs subtypes. The patterns of methylation strongly resemble that of primordial germ cells (PGC) at the migration phase, possibly indicating the cell of origin for these tumors. Unlike PGC, however, hypomethylation extends to long interspersed nuclear element retrotransposons. Histologically and epigenetically distinct microdissected components of mixed-GCTs shared identical somatic mutations in the MAPK or PI3K pathways, indicating that they developed from a common ancestral cell.

Recurrent neomorphic mutations of MTOR in central nervous system and testicular germ cell tumors may be targeted for therapy.

Germ cell tumors constitute a heterogeneous group that displays a broad spectrum of morphology. They often arise in testes; however, extragonadal occurrence, in particular brain, is not uncommon, and whether they share a common pathogenesis is unknown. We performed whole exome sequencing in 41 pairs of central nervous system germ cell tumors (CNS GCTs) of various histology and their matched normal tissues. We then performed targeted sequencing of 41 selected genes in a total of 124 CNS GCTs, 65 testicular germ cell tumors (tGCTs) and 8 metastatic GCTs to the CNS. The results showed that mutually exclusive mutations of genes involved in the MAPK pathway were most common (48.4 %), typically in KIT (27.4 %), followed by those in the PI3K pathway (12.9 %), particularly in MTOR (6.5 %), among the 124 CNS GCTs. Pure germinomas and non-germinomatous germ cell tumors (NGGCTs), as well as CNS and testicular GCTs, showed similar mutational profiles, suggesting that GCTs share a common molecular pathogenesis. Mutated MTOR identified in CNS GCTs upregulated phosphorylation of the AKT pathway proteins including AKT and 4EBP1 in nutrient-deprived conditions and enhanced soft-agar colony formation; both events were suppressed in a dose-dependent manner by addition of the MTOR inhibitor pp242. Our findings indicate that the dominant genetic drivers of GCTs regardless of the site of origin are activation of the MAPK and/or PI3K pathways by somatic point mutations. Mutated MTOR represents a potential target for novel targeted therapies for refractory GCTs.