Abstract
Classifying adult gliomas remains largely a histologic diagnosis based on morphology; however astrocytic, oligodendroglial and mixed lineage tumors can display overlapping histologic features. We used multiplexed exome sequencing (OncoPanel) on 108 primary or recurrent adult gliomas, comprising 65 oligodendrogliomas, 28 astrocytomas and 15 mixed oligoastrocytomas to identify lesions that could enhance lineage classification. Mutations in TP53 (20/28, 71%) and ATRX (15/28, 54%) were enriched in astrocytic tumors compared to oligodendroglial tumors of which 4/65 (6%) had mutations in TP53 and 2/65 (3%) had ATRX mutations. We found that oligoastrocytomas harbored mutations in TP53 (80%, 12/15) and ATRX (60%, 9/15) at frequencies similar to pure astrocytic tumors, suggesting that oligoastrocytomas and astrocytomas may represent a single genetic or biological entity. p53 protein expression correlated with mutation status and showed significant increases in astrocytomas and oligoastrocytomas compared to oligodendrogliomas, a finding that also may facilitate accurate classification. Furthermore our OncoPanel analysis revealed that 15% of IDH1/2 mutant gliomas would not be detected by traditional IDH1 (p.R132H) antibody testing, supporting the use of genomic technologies in providing clinically relevant data. In all, our results demonstrate that multiplexed exome sequencing can support evaluation and classification of adult low-grade gliomas with a single clinical test.
Highlights
Adult gliomas account for 20% of primary brain tumors, comprising a spectrum of tumors with varying grades (WHO Grade I-IV) and dramatic differences in patient outcomes and survival [1]
The most common mutations across the adult lower grade gliomas (ALGGs) cohort were IDH1 and IDH2, which collectively occurred in 90% (97/108) of tumors suggesting that formation of these neomorphic metabolic enzymes represents an early event in gliomagenesis
Our analysis of 108 ALGGs encompassing astrocytic, mixed and oligodendroglial lineage tumors revealed that TP53 mutations were most frequent in astrocytic and mixed lineage tumors but were rarely present in oligodendroglial tumors and when present were www.impactjournals.com/oncotarget only seen in anaplastic oligodendrogliomas, consistent with previous studies [19]
Summary
Adult gliomas account for 20% of primary brain tumors, comprising a spectrum of tumors with varying grades (WHO Grade I-IV) and dramatic differences in patient outcomes and survival [1]. Several recent reports have broadened our understanding of these tumors and highlighted the utility of large scale sequencing studies in identifying clinically distinct subgroups [4, 5]. These lower grade, infiltrating gliomas represent 15% of all primary brain tumors diagnosed in adults and typically manifest in younger patients (3rd and 4th decades) compared to GBMs which occur later in life (5th-7th decades) [6,7,8,9]; ALGGs can progress to higher grade lesions with resistance to standard of care therapies including radiation and chemotherapy. Diagnostic classification of oligoastrocytomas is associated with an inter-observer variability rate approaching 50%, demonstrating the need for objective biomarkers to aid prognostic and therapeutic decision-making [11, 12]
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