Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas

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.

Defining neoplastic diseases differently: An emerging paradigm from The Cancer Genome Atlas lower-grade gliomas project

“…In the past, there has been considerable inconsistency in diagnostic criteria for oligoastrocytomas, and many LGGs with "ambiguous morphology" received this diagnosis. [8][9][10] Our results indicated that…”

Oligoastrocytoma: A Vanishing Tumor Entity

“…The immunohistochemical evaluation of the ATRX protein expression could represent an alternative method to assess the ATRX status. Although studies reported concordant results between the mutation analysis and IHC [38,72], tumor heterogeneity in the ATRX expression and concurrent normal non-tumor cells with constitutive ATRX expression may explain possible discrepancy. As a matter of fact, ATRX mutations/ATRX protein loss characterizes astrocytic gliomas, whereas retained ATRX immunoreactivity characterizes oligodendroglial gliomas.…”

“…Restricted to IDH mutant tumors, they are significantly associated to TP53 mutations and nuclear p53 overexpression and to astrocytic differentiation; they are mutually exclusive with 1p/19q co-deletion [71,72]. ATRX and IDH1/2 mutations occur in association and they may represent early genetic alterations in the development of gliomas affecting progenitors before their differentiation along the two lineages.…”

“…ATRX loss is a prognostic factor in IDH mutant and non 1p/19q co-deleted low grade gliomas [62,65]. In GBMs, ATRX loss affects younger patients [72].…”

“…Anyway, there is no doubt on the usefulness of the ATRX IHC [72] and of the double ATRX/ IDH1 R132H immunostaining [77] in the diagnosis of adult diffuse gliomas. Based on molecular data from the above mentioned markers on 54 OAs, it has been concluded that OA represents a morphological grey zone rather than a group of truly "mixed" or "intermediate" gliomas [78].…”