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Molecular Classification of Glioma Based on IDH Mutation, 1p/19q Codeletion, and TERT Promoter Mutation Status

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Key Points

  • Molecular groups were associated with overall survival among patients with grades 2 and 3 but not grade 4 gliomas.
  • Molecular groups were associated with specific germline variants.

In a study reported in The New England Journal of Medicine, Eckel-Passow et al identified a molecular classification scheme for gliomas based on IDH mutation, codeletion of chromosome arms 1p and 19q (1p/19q codeletion), and TERT promoter mutation status.

Molecular Classification

The study involved 615 patients with grade II or III gliomas and 472 with grade IV gliomas. Among those with grade II or III gliomas, 29% had IDH mutation, 1p/19q codeletion, and TERT mutation (triple-positive), 5% had TERT and IDH mutations only, 45% had IDH mutation only, 7% were triple-negative, and 10% had TERT mutation only. Among patients with grade IV gliomas, < 1% were triple-positive, 2% had TERT and IDH mutations only, 7% had IDH mutation only, 17% were triple-negative, and 74% had TERT mutation only.

Mean age at diagnosis was lowest (37 years) among patients with only IDH mutations and highest (59 years) among those with only TERT mutations.

Associations With Survival

The molecular groups were independently associated with overall survival among patients with grade II or III gliomas, with poorest survival among patients with TERT mutation only. On multivariate analysis, compared with triple-positive patients, hazard ratios (HRs) for death were 1.31 (95% confidence interval [CI] = 0.55–3.12) among those with TERT and IDH mutations only, 2.08 (95% CI = 1.22–3.57) among those with IDH mutation only, 3.74 (95% CI= 1.91–7.36) among triple-negative patients, and 11.74 (95% CI = 6.15–22.41) among those with TERT mutation only. There was no significant association of molecular group with overall survival among patients with grade IV glioma.

Acquired Mutations and Germline Variants

Common acquired mutations were: CIC, FUBP1, NOTCH1, and PIK3CA or PIK3R1 in triple-positive patients; TP53 and ATRX in those with TERT and IDH mutations only and IDH mutation only; EGFR, PTEN, and NF1 in triple-negative patients; and EGFR, EGFRvIII, PTEN, NF1, RB1, and  PIK3CA or PIK3R1 in those with TERT mutation only.

Associations with molecular groups and known glioma germline variants were assessed using a group of 11,950 controls. Germline variants included 8q24 in triple-positive patients; 8q24 and TP53 3’ untranslated region in those with TERT and IDH mutations only; 8q24 and PHLDB1 in those with IDH mutation only; CDKN2A/B, RTEL1, and TERT in triple-negative patients; and CDKN2A/B, RTEL1, TERT, and TERC in those with TERT mutation only.

The investigators concluded: “Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis.”

Robert B. Jenkins, MD, PhD, of the Mayo Clinic, is the corresponding author for the New England Journal of Medicine article.

The study was funded by the National Institutes of Health and others. For full disclosures of the study authors, visit www.nejm.org.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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