Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors

By J. Eckel-Passow, D. Lachance, Annette M. Molinaro, K. Walsh, P. Decker, Hugues Sicotte, M. Pekmezci, T. Rice, M. Kosel, I. Smirnov and 26 more. New England Journal of Medicine, 2015

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BACKGROUND The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triplepositive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS 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.

Subfields: Genetics, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/1b47762cde5f04453cdb5e5d56aa3397987008c8

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Citations in the corpus

Glioma Subclassifications and Their Clinical Significance (2017, methodology): “Based on these findings, the presence of an isolated TERT mutation in a LGG may be an indicator that the clinical behavior of a tumor may be more akin to a grade IV tumor [30].”
Molecular profiling reveals biologically discrete subsets and pathways of progression in diffuse glioma (2016, neutral): “ATRX forms a complex with DAXX and H3.”
R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling (2017, background): “Interestingly, glioma patients with IDH lesions tend to have a better overall survival than those without (Brat et al., 2015; Eckel-Passow et al., 2015), and a similar trend, although still debatable (Marcucci et al.”
Association of genomic subtypes of lower-grade gliomas with shape features automatically extracted by a deep learning algorithm (2019, background): “Patients with tumors from different molecular groups substantially differ in terms of typical course of the disease and overall survival [3].”
Survival in glioblastoma: a review on the impact of treatment modalities (2016, background): “Recent studies on the molecular pathogenesis of gliomas have led to a re-classification of glial tumors according to three specific tumor markers: 1p/19q codeletion, either isocitrate dehydrogenase-1 (IDH1) or IDH2 mutation, and mutation of promoter of TERT (telomerase reverse transcriptase) [11].”