New Molecular Classifications of Gliomas Established


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The integration of genome-wide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class.

—The Cancer Genome Atlas Research Network

Two studies reported in The New England Journal of Medicine identified new molecular classifications of glioma that capture biologic and prognostic differences. The Cancer Genome Atlas Research Network identified three prognostically significant subtypes of lower-grade glioma that were identified by IDH mutation and codeletion of chromosome arms 1p and 19q (1p/19q codeletion) status.1 Jeanette E. Eckel-Passow, PhD, of the Mayo Clinic, Rochester, Minnesota, and colleagues identified five subtypes of glioma based on IDH mutation, 1p/19q codeletion, and TERT promoter mutation status.2

IDH Mutation and 1p/19q Codeletion

The Cancer Genome Atlas Research Network study1 involved genome-wide analysis of 293 diffuse grade II or III gliomas from adults, including analysis of exome sequence, DNA copy number, DNA methylation, messenger RNA expression, microRNA expression, and targeted protein expression. The investigators found that three primary lower-grade glioma classes were best represented by IDH and 1p/19q status, that lower-grade gliomas with IDH mutation had either 1p/19q codeletion or TP53 mutation in a mutually exclusive manner, and that the majority of lower-grade gliomas with wild-type IDH were genomically and clinically similar to primary glioblastoma.

Associations With Survival

Patients who had lower-grade gliomas with IDH mutation and 1p/19q codeletion had the best clinical outcomes; these patients had mutations in CIC, FUBP1, NOTCH1, and the TERT promoter. Almost all gliomas with IDH mutation and no 1p/19q codeletion had mutations in TP53 (94%) and ATRX inactivation (86%).

Patients with wild-type IDH had significantly shorter overall survival vs those with IDH mutation (age-adjusted hazard ratio [HR] = 7.4, 95% confidence interval [CI] = 4.0–13.8). Median overall survival in these patients was 1.7 years, compared with 6.3 years in patients with IDH mutation and no 1p/19q codeletion and 8.0 years in patients with IDH mutation and 1p/19q codeletion (P < .001 for trend). Survival in the lower-grade glioma patients with wild-type IDH was intermediate between that of patients with glioblastoma with wild-type IDH (median, 1.1 years) and glioblastoma patients with IDH mutation (median, 2.1 years).

In multiple-predictor models adjusting for age and extent of resection, wild-type IDH, IDH mutation with no 1p/19q codeletion, or IDH mutation with 1p/19q codeletion accurately stratified patient outcomes. Grade, but not histologic class, was a significant predictor of outcome in multivariate analysis including IDH and 1p/19q status.

The investigators concluded: “The integration of genome-wide data from multiple platforms delineated three molecular classes of lower-grade gliomas that were more concordant with IDH, 1p/19q, and TP53 status than with histologic class. Lower-grade gliomas with an IDH mutation either had 1p/19q codeletion or carried a TP53 mutation. Most lower-grade gliomas without an IDH mutation were molecularly and clinically similar to glioblastoma.”

IDH or TERT Mutation and 1p/19q Codeletion

The study reported by Eckel-Passow and colleagues2 involved 615 patients with grade 2 or 3 gliomas and 472 with grade 4 gliomas. Among those with grade 2 or 3 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 4 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 2 or 3 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. In grade 4 gliomas, molecular group is associated with overall survival. However, in the multivariable model, molecular group is no longer associated with overall survival; in the multivariable model, only age is statistically significant.

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.” ■

Disclosure: The Cancer Genome Atlas Research Network study was funded by the National Institutes of Health. The study reported by Eckel-Passow and colleagues was supported by the National Institutes of Health and others. For full disclosures of the study authors, visit www.nejm.org.

References

1. The Cancer Genome Atlas Research Network: Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481-2498, 2015.

2. Eckel-Passow JE, Lachance DH, Molinaro AM, et al: Glioma groups based on 1p/19q, IDH, and TERT promoter mutations in tumors. N Engl J Med 372:2499-2508, 2015.

Mark R. Gilbert, MD, of the National Institutes of Health, discusses our improved understanding of glioma tumor biology.


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