Distinct molecular profile of diffuse cerebellar gliomas

Abstract

Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions. Frequent mutations in chromatin-modifier genes were identified including, noticeably, a truncating mutation in SETD2 (n = 4), which resulted in loss of H3K36 trimethylation and was mutually exclusive with H3F3A K27M mutation (n = 3), suggesting that epigenetic dysregulation may lead to DCG tumorigenesis. Alterations that cause loss of p53 function including TP53 mutation (n = 9), PPM1D mutation (n = 2), and a novel type of PPM1D fusion (n = 1), were also frequent. On the other hand, mutations and copy number changes commonly observed in cerebral gliomas were infrequent. DNA methylation profile analysis demonstrated that all DCGs except for those with H3F3A mutations were categorized in the “RTK I (PDGFRA)” group, and those DCGs had a gene expression signature that was highly associated with PDGFRA. Furthermore, compared with the data of 315 gliomas derived from different brain regions, promoter methylation of transcription factors genes associated with glial development showed a characteristic pattern presumably reflecting their tumor origin. Notably, SOX10, a key transcription factor associated with oligodendroglial differentiation and PDGFRA regulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline glioma, suggesting their developmental and biological commonality. In contrast, SOX10 was silenced by promoter methylation in most cerebral gliomas. These findings may suggest potential tailored targeted therapy for gliomas according to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-017-1771-1) contains supplementary material, which is available to authorized users.

Cerebellar high‐grade astrocytoma with IDH mutations in the elderly: A report of two cases

“…[1][2][3][4]12 Because of its rarity, the nature of the cerebel- no tumors with an IDH1/2 mutation. 8 Nakata et al also detected two H3F3A K27M mutated tumors among 10 cerebellar high-grade glioma cases, 11 in which our two IDHmutated tumors were included. In diffuse glioma, the IDH status is essential for integrated diagnosis by the WHO classification system (2016).…”

“…5 IDH mutations are often detected in grade II or III diffuse glioma and secondary glioblastoma. 1,4,[6][7][8] In addition, there are only a few reports of IDH-mutated diffuse gliomas of infratentorial origin. [14][15][16] In cerebellar high-grade gliomas, IDH mutations are rarely reported.…”

“…[1][2][3][4] Cerebellar highgrade gliomas are likely to affect younger patients compared with those of supratentorial origin 1,3 ; however, the clinicopathological and molecular genetic features of these tumors are poorly understood because of their rarity. 1,4,[6][7][8] Here, we present two unusual cases in elderly patients with a mutation in IDH1 or IDH2. 5 Some recent reports investigated IDH1/2 in cerebellar highgrade gliomas immunohistochemically or genetically and revealed that IDH1/2 mutations were extremely rare.…”

“…5 Some recent reports investigated IDH1/2 in cerebellar highgrade gliomas immunohistochemically or genetically and revealed that IDH1/2 mutations were extremely rare. 1,4,[6][7][8] Here, we present two unusual cases in elderly patients with a mutation in IDH1 or IDH2.…”

cIMPACT-NOW update 3: recommended diagnostic criteria for “Diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”

“…Signatures predictive of aggressive clinical behavior will not apply to most pediatric diffuse gliomas and may not be relevant to diffuse gliomas arising in other less common sites. For example, IDH-wildtype diffuse astrocytic gliomas that arise in the cerebellum of adults are rare, and recent studies indicate that they do not harbor the same percentage of EGFR amplification, +7/−10, or TERT promoter mutations as their supratentorial counterparts[22, 23]. A subset will harbor H3 K27 or SETD2 mutations, but the full spectrum of their other alterations have not been defined, nor have the genetic events corresponding to aggressive behavior.…”