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      IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas

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          Abstract

          Background

          Epigenetic, genetic, and molecular studies have identified several diagnostic and prognostic markers in diffuse gliomas. Their importance for evaluating WHO grade II gliomas has yet to be specifically delineated.

          Methods

          We analyzed markers, including IDH mutation(IDHmut), 1p19q codeletion(1p19qcodel), ATRX expression loss(ATRX loss) and p53 overexpression, and outcomes in 159 patients with WHO grade II oligodendroglioma, oligoastrocytoma, and astrocytoma (2003–2012).

          Results

          IDHmut was found in 141(91%) and ATRX loss in 64(87%) of IDHmut-noncodel tumors ( p = 0.003). All codeleted tumors ( n = 66) were IDHmut. Four subgroups were identified: IDHmut-codel, 66(43%); IDHmut-noncodel-ATRX loss, 60(39%); IDHmut-noncodel-ATRXwt, 9(6%); IDHwt, 14(9%). Median survival among 4 groups was significantly different ( p = 0.038), particularly in IDHmut-codel (median survival 15.6 years) compared to the remaining 3 groups ( p = 0.025). Survival by histology was not significant. Overall (OS), but not progression-free (PFS), survival was significantly longer with gross total resection vs. biopsy only ( p = 0.042). Outcomes for patients with subtotal resection were not significantly different from those with biopsy only. Among these uniformly treated patients, OS far exceeds PFS, particularly in those with 1p/19q codeletion.

          Conclusions

          For WHO grade II diffuse glioma, molecular classification using 1p/19qcodel, IDHmut, and ATRX loss more accurately predicts outcome and should be incorporated in the neuropathologic evaluation.

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          Most cited references19

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          Type and frequency of IDH1 and IDH2 mutations are related to astrocytic and oligodendroglial differentiation and age: a study of 1,010 diffuse gliomas.

          Christian Johannes Hartmann, Jochen Meyer, Jörg Balss … (2009)
          Somatic mutations in the IDH1 gene encoding cytosolic NADP+-dependent isocitrate dehydrogenase have been shown in the majority of astrocytomas, oligodendrogliomas and oligoastrocytomas of WHO grades II and III. IDH2 encoding mitochondrial NADP+-dependent isocitrate dehydrogenase is also mutated in these tumors, albeit at much lower frequencies. Preliminary data suggest an importance of IDH1 mutation for prognosis showing that patients with anaplastic astrocytomas, oligodendrogliomas and oligoastrocytomas harboring IDH1 mutations seem to fare much better than patients without this mutation in their tumors. To determine mutation types and their frequencies, we examined 1,010 diffuse gliomas. We detected 716 IDH1 mutations and 31 IDH2 mutations. We found 165 IDH1 (72.7%) and 2 IDH2 mutations (0.9%) in 227 diffuse astrocytomas WHO grade II, 146 IDH1 (64.0%) and 2 IDH2 mutations (0.9%) in 228 anaplastic astrocytomas WHO grade III, 105 IDH1 (82.0%) and 6 IDH2 mutations (4.7%) in 128 oligodendrogliomas WHO grade II, 121 IDH1 (69.5%) and 9 IDH2 mutations (5.2%) in 174 anaplastic oligodendrogliomas WHO grade III, 62 IDH1 (81.6%) and 1 IDH2 mutations (1.3%) in 76 oligoastrocytomas WHO grade II and 117 IDH1 (66.1%) and 11 IDH2 mutations (6.2%) in 177 anaplastic oligoastrocytomas WHO grade III. We report on an inverse association of IDH1 and IDH2 mutations in these gliomas and a non-random distribution of the mutation types within the tumor entities. IDH1 mutations of the R132C type are strongly associated with astrocytoma, while IDH2 mutations predominantly occur in oligodendroglial tumors. In addition, patients with anaplastic glioma harboring IDH1 mutations were on average 6 years younger than those without these alterations.
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            A t(1;19)(q10;p10) mediates the combined deletions of 1p and 19q and predicts a better prognosis of patients with oligodendroglioma.

            Robert B. Jenkins, Hilary Blair, Karla V. Ballman … (2006)
            Combined deletion of chromosomes 1p and 19q is associated with improved prognosis and responsiveness to therapy in patients with anaplastic oligodendroglioma. The deletions usually involve whole chromosome arms, suggesting a t(1;19)(q10;p10). Using stem cell medium, we cultured a few tumors. Paraffin-embedded tissue was obtained from 21 Mayo Clinic patients and 98 patients enrolled in 2 North Central Cancer Treatment Group (NCCTG) low-grade glioma trials. Interphase fusion of CEP1 and 19p12 probes detected the t(1;19). 1p/19q deletions were evaluated by fluorescence in situ hybridization. Upon culture, one oligodendroglioma contained an unbalanced 45,XX,t(1;19)(q10;p10). CEP1/19p12 fusion was observed in all metaphases and 74% of interphase nuclei. Among Mayo Clinic oligodendrogliomas, the prevalence of fusion was 81%. Among NCCTG patients, CEP1/19p12 fusion prevalence was 55%, 47%, and 0% among the oligodendrogliomas, mixed oligoastrocytomas, and astrocytomas, respectively. Ninety-one percent of NCCTG gliomas with 1p/19q deletion and 12% without 1p/19q deletion had CEP1/19p12 fusion (P < 0.001, chi(2) test). The median overall survival (OS) for all patients was 8.1 years without fusion and 11.9 years with fusion (P = 0.003). The median OS for patients with low-grade oligodendroglioma was 9.1 years without fusion and 13.0 years with fusion (P = 0.01). Similar significant median OS differences were observed for patients with combined 1p/19q deletions. The absence of alterations was associated with a significantly shorter OS for patients who received higher doses of radiotherapy. Our results strongly suggest that a t(1;19)(q10;p10) mediates the combined 1p/19q deletion in human gliomas. Like combined 1p/19q deletion, the 1;19 translocation is associated with superior OS and progression-free survival in low-grade glioma patients.
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              Benefit from procarbazine, lomustine, and vincristine in oligodendroglial tumors is associated with mutation of IDH.

              David Brachman, Jan Buckner, Caterina Giannini … (2014)
              Patients with 1p/19q codeleted anaplastic oligodendroglial tumors who participated in RTOG (Radiation Therapy Oncology Group) 9402 lived much longer after chemoradiotherapy (CRT) than radiation therapy (RT) alone. However, some patients with noncodeleted tumors also benefited from CRT; survival curves separated after the median had been reached, and significantly more patients lived ≥ 10 years after CRT than RT. Thus, 1p/19q status may not identify all responders to CRT. Using trial data, we inquired whether an IDH mutation or germ-line polymorphism associated with IDH-mutant gliomas identified the patients in RTOG 9402 who benefited from CRT. IDH status was evaluable in 210 of 291 patients; 156 (74%) had mutations. rs55705857 was evaluable in 245 patients; 76 (31%) carried the G risk allele. Both were associated with longer progression-free survival after CRT, and mutant IDH was associated with longer overall survival (9.4 v 5.7 years; hazard ratio [HR], 0.59; 95% CI, 0.40 to 0.86; P = .006). For those with wild-type tumors, CRT did not prolong median survival (1.3 v 1.8 years; HR, 1.14; 95% CI, 0.63 to 2.04; P = .67) or 10-year survival rate (CRT, 6% v RT, 4%). Patients with codeleted mutated tumors (14.7 v 6.8 years; HR, 0.49; 95% CI, 0.28 to 0.85; P = .01) and noncodeleted mutated tumors (5.5 v 3.3 years; HR, 0.56; 95% CI, 0.32 to 0.99; P < .05) lived longer after CRT than RT. IDH mutational status identified patients with oligodendroglial tumors who did (and did not) benefit from alkylating-agent chemotherapy with RT. Although patients with codeleted tumors lived longest, patients with noncodeleted IDH-mutated tumors also lived longer after CRT.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Oncotarget
                Journal ID (iso-abbrev): Oncotarget
                Journal ID (publisher-id): ImpactJ
                Title: Oncotarget
                Publisher: Impact Journals LLC
                ISSN (Electronic): 1949-2553
                Publication date Collection: 6 October 2015
                Publication date (Electronic): 3 July 2015
                Volume: 6
                Issue: 30
                Pages: 30295-30305
                Affiliations
                1 Neuro-Oncology, Advocate Medical Group, Park Ridge, IL 60068, USA
                2 Experimental Pathology, Mayo Clinic SW, Rochester, MN 55905, USA
                3 Biomedical Statistics and Informatics, Mayo Clinic SW, Rochester, MN 55905, USA
                4 Neurology, Mayo Clinic SW, Rochester, MN 55905, USA
                5 Anatomic Pathology, Mayo Clinic SW, Rochester, MN 55905, USA
                Author notes
                Correspondence to: Caterina Giannini, giannini.caterina@ 123456mayo.edu
                Article
                DOI: 10.18632/oncotarget.4497
                PMC ID: 4745799
                PubMed ID: 26210286
                SO-VID: c02b3253-eab1-463c-906e-58bd31d2b4d7
                Copyright © Copyright: © 2015 Leeper et al.
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 12 March 2015
                Date accepted : 22 June 2015
                Categories
                Subject: Clinical Research Paper

                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: diffuse gliomas,who grade ii,idh mutation,atrx,1p19q codeletion
                Data availability:
                ScienceOpen disciplines: Oncology & Radiotherapy
                Keywords: diffuse gliomas, who grade ii, idh mutation, atrx, 1p19q codeletion

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