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

Abstract

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 triple-positive), 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. (Funded by the National Institutes of Health and others.).

Figure 1. Prevalence of the Glioma Molecular Groups in the Combined Sample

The prevalence of the molecular groups among gliomas of grade II or III (astrocytomas, mixed oligoastrocytomas, and oligodendrogliomas), grade IV (glioblastoma multiforme), and grades II through IV combined is shown.

Figure 2. Mean Age at Diagnosis for Each Glioma Molecular Group

Data from three glioma case series were used: the Mayo Clinic; the University of California, San Francisco (UCSF), Adult Glioma Study; and the Cancer Genome Atlas. Vertical lines represent standard deviations.

Figure 3. Adjusted Kaplan–Meier Estimates of Overall Survival in the Glioma Molecular Groups

Overall survival estimates were adjusted for sex and age at diagnosis (on the basis of the 2010 U.S. white population) with the use of the reweighted (direct adjustment) method. Because there was only one triple-positive case among patients with grade IV gliomas, this group was not included in Panel B.

Figure 4. Associations between Glioma Molecular Groups and Glioma-Related SNPs

Shown are the odds ratios for the five molecular groups of glioma for each of the single-nucleotide polymorphisms (SNPs) that have been found in case–control studies to be associated with glioma. Only SNPs with a P value of 0.0011 or lower (Bonferroni-corrected P value for testing nine regions in each of the five molecular groups) are shown. Vertical lines indicate the 95% confidence intervals associated with the odds ratios. For this figure, the cases and controls from Mayo Clinic, UCSF Adult Glioma Study, the Cancer Genome Atlas, and the Mayo Genome Consortia were combined. See Figure S7 in Supplementary Appendix for an illustration of results for the nine regions for all five glioma groups. See Table S6 in Supplementary Appendix for a complete summary of the data for all 22 SNPs evaluated.