Chromothripsis is rare in IDH-mutant gliomas compared to IDH-wild-type glioblastomas whereas whole-genome duplication is equally frequent in both tumor types.

Background: Adult-type diffuse gliomas comprise IDH (isocitrate dehydrogenase)-mutant astrocytomas, IDH-mutant 1p/19q-codeleted oligodendrogliomas (ODG), and IDH-wild-type glioblastomas (GBM). GBM displays genome instability, which may result from 2 genetic events leading to massive chromosome alterations: Chromothripsis (CT) and whole-genome duplication (WGD). These events are scarcely described in IDH-mutant gliomas. The better prognosis of the latter may be related to their genome stability compared to GBM. Methods: Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening. Survival data were compared using the Kaplan-Meier method. Results: At initial diagnosis, 37 GBM (18.7%) displayed CT versus 5 IDH-mutant gliomas (4.7%; P = .0008), the latter were all high-grade (grade 3 or 4) astrocytomas. WGD was detected at initial diagnosis in 18 GBM (9.3%) and 9 IDH-mutant gliomas (5 astrocytomas and 4 oligodendrogliomas, either low- or high-grade; 8.5%). Neither CT nor WGD was associated with overall survival in GBM or in IDH-mutant gliomas. Conclusions: CT is less frequent in IDH-mutant gliomas compared to GBM. The absence of CT in ODG and grade 2 astrocytomas might, in part, explain their genome stability and better prognosis, while CT might underlie aggressive biological behavior in some high-grade astrocytomas. WGD is a rare and early event occurring equally in IDH-mutant gliomas and GBM.

[Tyrosine kinase receptor gene fusion: A series of four cases of infantile-type hemispheric glioma]. / Gènes de fusion à activité tyrosine kinase : une série de quatre cas de gliome hémisphérique infantile.

INTRODUCTION: Infant-type hemispheric gliomas belong to pediatric-type diffuse high-grade gliomas according to the 2021 WHO classification of central nervous system tumors. They are characterized by tyrosine kinase gene rearrangements (NTRK1/2/3, ALK, ROS1, MET). The aim of the study was to describe the clinical, histopathologic, and molecular characteristics of such tumors, and to provide a review of the literature. PATIENTS AND METHODS: This retrospective series comprises four cases of infant-type hemispheric glioma diagnosed at Angers University Hospital between 2020 and 2022. The diagnosis was suspected based on morphology and immunohistochemistry and was confirmed by molecular biology techniques. RESULTS: The most common clinical sign was raised intracranial pressure. Imaging showed a large cerebral hemispheric tumor with contrast enhancement. Microscopic examination revealed diffuse astrocytoma with high-grade features, sometimes with neuronal or pseudo-ependymal differentiation. Identification of a gene fusion involving a tyrosine kinase gene allowed to make a definitive diagnosis of infant-type hemispheric glioma. DISCUSSION AND CONCLUSION: Infant-type hemispheric gliomas are rare and present as large cerebral hemispheric tumors in very young children. Searching for a tyrosine kinase gene fusion should be systematic when dealing with a high-grade glioma in an infant. Importantly, these gene fusions are therapeutic targets. The impact of targeted therapies on patient survival should be evaluated in future prospective studies.

Mitochondrial DNA copy number as a prognostic marker is age-dependent in adult glioblastoma.

BACKGROUND: Glioblastoma (GBM) is the most common and aggressive form of glioma. GBM frequently displays chromosome (chr) 7 gain, chr 10 loss and/or EGFR amplification (chr7+/chr10-/EGFRamp). Overall survival (OS) is 15 months after treatment. In young adults, IDH1/2 mutations are associated with longer survival. In children, histone H3 mutations portend a dismal prognosis. Novel reliable prognostic markers are needed in GBM. We assessed the prognostic value of mitochondrial DNA (mtDNA) copy number in adult GBM. METHODS: mtDNA copy number was assessed using real-time quantitative PCR in 232 primary GBM. Methylation of POLG and TFAM genes, involved in mtDNA replication, was assessed by bisulfite-pyrosequencing in 44 and 51 cases, respectively. RESULTS: Median age at diagnosis was 56.6 years-old and median OS, 13.3 months. 153/232 GBM (66 %) displayed chr7+/chr10-/EGFRamp, 23 (9.9 %) IDH1/2 mutation, 3 (1.3 %) H3 mutation and 53 (22.8 %) no key genetic alterations. GBM were divided into two groups, "Low" (n = 116) and "High" (n = 116), according to the median mtDNA/nuclear DNA ratio (237.7). There was no significant difference in OS between the two groups. By dividing the whole cohort according to the median age at diagnosis, OS was longer in the "High" vs "Low" subgroup (27.3 vs 15 months, P = .0203) in young adult GBM (n = 117) and longer in the "Low" vs "High" subgroup (14.5 vs 10.2 months, P = .0116) in older adult GBM (n = 115). POLG was highly methylated, whereas TFAM remained unmethylated. CONCLUSION: mtDNA copy number may be a novel prognostic biomarker in GBM, its impact depending on age.

[Hereditary predisposition to tumors of the central and peripheral nervous systems]. / Prédisposition héréditaire aux tumeurs des systèmes nerveux central et périphérique.

Some tumors of the central and peripheral nervous system may be associated with a cancer predisposition syndrome, either hereditary or occurring de novo. Such a syndrome is usually associated with multiple tumors occurring early in life. Patients with neurofibromatosis type 1 present with multiple neurofibromas, especially of the plexiform type (which may transform into malignant peripheral nerve sheath tumor), and pilocytic astrocytomas of the optic pathways. Neurofibromatosis type 2 patients present with multiple schwannomas (typically bilateral vestibular schwannomas), meningiomas, and ependymomas. Li-Fraumeni syndrome (germline TP53 mutation) is associated with choroid plexus tumors (carcinomas), medulloblastomas, and diffuse astrocytomas. Multiple hemangioblastomas are characteristic of von Hippel-Lindau syndrome while subependymal giant cell astrocytomas are pathognomonic of tuberous sclerosis complex. Dysplastic cerebellar gangliocytomas of adult patients occur in Cowden syndrome. Turcot syndrome overlaps with constitutional mismatch repair deficiency syndrome (CMMRD), which is associated with giant cell glioblastomas. Rhabdoid tumor predisposition syndrome (germline mutation of SMARCB1/INI1) is associated with atypical teratoid/rhabdoid tumors. Tumors arising in the setting of a cancer predisposition syndrome develop along specific genetic pathways. Some histopathological and immunohistochemical characteristics of these tumors may point toward such a syndrome. The diagnosis of a cancer predisposition syndrome is of tremendous importance to the patients and their families who require genetic counseling and long-term follow-up.