IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival

Leu, Severina; Felten, Stefanie von; Frank, Stephan; Vassella, Erik; Vajtai, István; Taylor, Elisabeth; Schulz, Marianne; Hütter, Gregor; Hench, Jürgen; Schucht, Philippe; Boulay, Jean-Louis; Mariani, Luigi

doi:10.1093/neuonc/nos317

Cited by 164 publications

(118 citation statements)

References 36 publications

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“…Consistent with prior analysis [5], it was observed in our cohort that the presence of IDH1 mutation status was associated with better OS and PFS (3-year OS for IDH1 (n=7) vs. no IDH1 (n=6): 100% vs. 21%, 3-year PFS for IDH1 (n=7) vs. no IDH1 (n=6): 67% vs. 0%). With respect to 1p19q deletion status, overall survival was improved but was not significantly different [22]. Despite previous studies that indicate that median survival in patients with diagnosed 1p and 19q deletion is twice as long in comparison with patients in whom no deletion was observed, our study did not find such a significant difference [11].…”

Section: Discussioncontrasting

confidence: 95%

Prognosis of older patients with low-grade glioma: A retrospective study

Kumthekar¹,

Patel²,

Bridge³

et al. 2017

Integr Cancer Sci Therap

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Section: Discussioncontrasting

confidence: 95%

Prognosis of older patients with low-grade glioma: A retrospective study

Kumthekar¹,

Patel²,

Bridge³

et al. 2017

Integr Cancer Sci Therap

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“…The exact role that IDH1 mutations serve in neoplasia is not fully understood, however it has been demonstrated that presence of a heterozygous R132H mutation induces genome-wide alterations in DNA methylation, leading to hypermethylation and hypomethylation (16,17). IDH1 mutations are associated with MGMT and CRBP1 promoter methylation in certain brain tumors (18)(19)(20)(21). However, this association was not observed in the periosteal chondroma tissue specimens in the present study, since none of them possessed methylated MGMT or CRBP1 promoters, as determined using the MSP methodology (11,12).…”

Section: Discussionmentioning

confidence: 99%

Recurrent 12q13-15 chromosomal aberrations, high frequency of isocitrate dehydrogenase 1 mutations, and absence of high mobility group AT-hook 2 expression in periosteal chondromas

et al. 2015

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Abstract. Periosteal chondroma is a benign cartilage tumor that accounts for <2% of chondromas. In the present study, four cases of periosteal chondromas were cytogenetically investigated and studied for the expression of high-mobility group AT-hook 2 (HMGA2), mutations in codons 132 of isocitrate dehydrogenase (IDH)1 and 172 of IDH2; mutations -C228T and -C250T in the promoter region of telomerase reverse transcriptase (TERT); and for methylation in the promoter regions of O-6-methylguanine-DNA methyltransferase (MGMT) and cellular retinol binding protein 1 (CRBP1). Chromosome aberrations of 12q13-15 were found in two out of the four tumors, while two had a normal karyotype. Two periosteal chondromas carried the mutation IDH1R132C (CGT>TGT), and two carried the mutation IDH1R132L (CGT>CTT). However, none of the four tumors had methylated MGMT and CRBP1 promoters or mutations at codon 172 of IDH2. In addition, -C228T and -C250T mutations were not present in the promoter region of TERT, nor was HMGA2 demonstrated to be expressed. The present study indicated that in periosteal chondromas, the involvement of 12q13-15 in structural rearrangements may be recurrent but that HMGA2 is not expressed. Additionally, the periosteal chondromas investigated in the study carried a heterozygous IDH1R132 mutation, the MGMT and CRBP1 promoters were not methylated, and -C228T and -C250T mutations in the promoter region of TERT were absent.

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“…Second, assessment of O 6 -DNA methylguanine-methyltransferase (MGMT) methylation status, which has been previously associated with benefit to therapy with TMZ, 13 was not evaluated in this study as a potential prognostic factor. However, the presence of MGMT methylation has been found to be highly correlated with IDH mutational status 39 (84% of patients with IDH mutation were MGMT RT, radiotherapy; UCSF, University of California, San Francisco; GTR, gross total resection; STR, subtotal resection; NR, not reached. methylated), so MGMT status would likely provide minimal additional prognostic information.…”

Section: Neurooncologymentioning

confidence: 99%

Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide

Wahl

Phillips

Molinaro

et al. 2016

NEUONC

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Background. Optimal adjuvant management of adult low-grade gliomas is controversial. Recently described tumor classification based on molecular subtype has the potential to individualize adjuvant therapy but has not yet been evaluated as part of a prospective trial. Methods. Patients aged 18 or older with newly diagnosed World Health Organization grade II low-grade gliomas and gross residual disease after surgical resection were enrolled in the study. Patients received monthly cycles of temozolomide for up to 1 year or until disease progression. For patients with available tissue, molecular subtype was assessed based upon 1p/19q codeletion and isocitrate dehydrogenase-1 R132H mutation status. The primary outcome was radiographic response rate; secondary outcomes included progression-free survival (PFS) and overall survival (OS). Results. One hundred twenty patients were enrolled with median follow-up of 7.5 years. Overall response rate was 6%, with median PFS and OS of 4.2 and 9.7 years, respectively. Molecular subtype was associated with rate of disease progression during treatment (P<.001), PFS (P=.007), and OS (P<.001). Patients with 1p/19q codeletion demonstrated a 0% risk of progression during treatment. In an exploratory analysis, pretreatment lesion volume was associated with both PFS (P<.001) and OS (P<.001). Conclusions. While our study failed to meet the primary endpoint for objective radiographic response, patients with high-risk low-grade glioma receiving adjuvant temozolomide demonstrated a high rate of radiographic stability and favorable survival outcomes while meaningfully delaying radiotherapy. Patients with 1p/19q codeletion are potential candidates for omission of adjuvant radiotherapy, but further work is needed to directly compare chemotherapy with combined modality therapy.

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IDH/MGMT-driven molecular classification of low-grade glioma is a strong predictor for long-term survival

Abstract: By integrating networks of activated molecular glioma pathways, the model based on genotype better predicts prognosis than histology and, therefore, provides a more reliable tool for standardizing future treatment strategies.

Cited by 164 publications

References 36 publications

Prognosis of older patients with low-grade glioma: A retrospective study

Prognosis of older patients with low-grade glioma: A retrospective study

Recurrent 12q13-15 chromosomal aberrations, high frequency of isocitrate dehydrogenase 1 mutations, and absence of high mobility group AT-hook 2 expression in periosteal chondromas

Chemotherapy for adult low-grade gliomas: clinical outcomes by molecular subtype in a phase II study of adjuvant temozolomide

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