Distinct molecular profile of diffuse cerebellar gliomas
2017
Recent studies have demonstrated that tumor-driving alterations are often different among
gliomasthat originated from different brain regions and have underscored the importance of analyzing molecular characteristics of
gliomasstratified 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
gliomasin 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
gliomaswere 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
gliomasderived 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
PDGFRAregulation, was up-regulated in both DCG and H3 K27M-mutant diffuse midline
glioma, suggesting their developmental and biological commonality. In contrast,
SOX10was silenced by promoter methylation in most cerebral
gliomas. These findings may suggest potential tailored targeted therapy for
gliomasaccording to their brain region, in addition to providing molecular clues to identify the region-related cellular origin of DCGs.
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