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Comparative Study
. 2014 Sep 30;5(18):8083-92.
doi: 10.18632/oncotarget.2342.

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

Jane B Cryan  1 , Sam Haidar  2 , Lori A Ramkissoon  2 , Wenya Linda Bi  3 , David S Knoff  2 , Nikolaus Schultz  4 , Malak Abedalthagafi  1 , Loreal Brown  2 , Patrick Y Wen  2 , David A Reardon  2 , Ian F Dunn  3 , Rebecca D Folkerth  1 , Sandro Santagata  5 , Neal I Lindeman  1 , Azra H Ligon  1 , Rameen Beroukhim  2 , Jason L Hornick  1 , Brian M Alexander  6 , Keith L Ligon  7 , Shakti H Ramkissoon  7
Affiliations
Comparative Study

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

Jane B Cryan et al. Oncotarget. .

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.

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Figures

Figure 1
Figure 1. (A, B) Oncoprint diagramming TP53, ATRX and PTEN mutational status from 108 ALGGs categorized by lineage (A) or WHO grade (B)
Gray boxes represent individual tumors and green boxes indicate presence of a mutation. (C) Table summarizing TP53, ATRX and PTEN mutations occurring singly or in combination across all tumor classes.
Figure 2
Figure 2. (A) Representative H&E, p53 and ATRX images from IHC analysis on tumors from each diagnostic category
(B) Quantification of p53 demonstrates significant increases in nuclear positivity in astrocytic and mixed lineage tumors compared to oligodendroglial tumors, while ATRX expression is significantly increased in oligodendrogliomas (C). (D) p53 expression significantly correlated with TP53 mutations whereas ATRX expression was independent of mutation status across ALGG cohort (E).
Figure 3
Figure 3. (A, B) Oncoprint diagramming IDH1 and IDH2 mutational status from 108 ALGGs categorized by lineage (A) or WHO grade (B)
(C) Table summarizing IDH1 and IDH2 mutations across all tumor classes. (D) Graph representing frequency of IDH1 and IDH2 variants in each diagnostic category.
Figure 4
Figure 4. Table summarizing copy number alterations and mutations in IDH1/2 wildtype ALGGs
Figure 5
Figure 5. Schematic proposing an integrated classification for distinguishing ALGGs utilizing IDH1/2, TP53, ATRX and EGFR mutation status
See this image and copyright information in PMC

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