Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors - PubMed (original) (raw)
. 2015 Jun 25;372(26):2499-508.
doi: 10.1056/NEJMoa1407279. Epub 2015 Jun 10.
Daniel H Lachance, Annette M Molinaro, Kyle M Walsh, Paul A Decker, Hugues Sicotte, Melike Pekmezci, Terri Rice, Matt L Kosel, Ivan V Smirnov, Gobinda Sarkar, Alissa A Caron, Thomas M Kollmeyer, Corinne E Praska, Anisha R Chada, Chandralekha Halder, Helen M Hansen, Lucie S McCoy, Paige M Bracci, Roxanne Marshall, Shichun Zheng, Gerald F Reis, Alexander R Pico, Brian P O'Neill, Jan C Buckner, Caterina Giannini, Jason T Huse, Arie Perry, Tarik Tihan, Mitchell S Berger, Susan M Chang, Michael D Prados, Joseph Wiemels, John K Wiencke, Margaret R Wrensch, Robert B Jenkins
Affiliations
- PMID: 26061753
- PMCID: PMC4489704
- DOI: 10.1056/NEJMoa1407279
Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors
Jeanette E Eckel-Passow et al. N Engl J Med. 2015.
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.).
Figures
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.
Comment in
- Multiple Molecular Data Sets and the Classification of Adult Diffuse Gliomas.
Ellison DW. Ellison DW. N Engl J Med. 2015 Jun 25;372(26):2555-7. doi: 10.1056/NEJMe1506813. Epub 2015 Jun 10. N Engl J Med. 2015. PMID: 26061754 No abstract available. - CNS cancer: molecular classification of glioma.
Killock D. Killock D. Nat Rev Clin Oncol. 2015 Sep;12(9):502. doi: 10.1038/nrclinonc.2015.111. Epub 2015 Jul 14. Nat Rev Clin Oncol. 2015. PMID: 26169923 No abstract available. - TP53 and Histone H3.3 Mutations in Triple-Negative Lower-Grade Gliomas.
Chan AK, Mao Y, Ng HK. Chan AK, et al. N Engl J Med. 2016 Dec 1;375(22):2206-2208. doi: 10.1056/NEJMc1610144. N Engl J Med. 2016. PMID: 27959765 No abstract available.
References
- Phillips HS, Kharbanda S, Chen R, et al. Molecular subclasses of high-grade glioma predict prognosis, delineate a pattern of disease progression, and resemble stages in neurogenesis. Cancer Cell. 2006;9:157–73. - PubMed
- Jenkins RB, Blair H, Ballman KV, et al. A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma. Cancer Res. 2006;66:9852–61. - PubMed
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