DNA methylation profiling for molecular classification of adult diffuse lower-grade gliomas

Vega, Sandra Ferreyra; Bontell, Thomas Olsson; Corell, Alba; Smits, Anja; Jakola, Asgeir Store; Carén, Helena

doi:10.1186/s13148-021-01085-7

Cited by 30 publications

(29 citation statements)

References 39 publications

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“…In our cohort, the methylation profiles of only a small percentage of cases (30%) when uploaded to the DKFZ Classifier reached a calibration score of >0.84. The use of methylation profiling in diagnostic situations can be tumour‐type dependent, but it has been shown to be a very useful tool in diagnostic practice for brain tumours in many studies [57–62]. In our cohort, the tSNE assignment of clusters was useful, and the other genetic findings did not differ much between tumours with high (>0.84) and without high (<0.84) calibrated scores.…”

Section: Discussionmentioning

confidence: 70%

Molecular landscape of IDH‐wild‐type, H3‐wild‐type glioblastomas of adolescents and young adults

Shi

Huang

et al. 2022

Neuropathology Appl Neurobio

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Objective We aimed to characterise glioblastomas of adolescents and young adults (AYAs) that were isocitrate dehydrogenase (IDH) wild type (wt) and H3wt. Materials and Methods Fifty such patients (aged 16–32) were studied by methylation profiling, targeted sequencing and targeted RNA‐seq. Results Tumours predominantly clustered into three methylation classes according to the terminology of Capper et al. (2018): (anaplastic) pleomorphic xanthoastrocytoma (PXA) (21 cases), GBM_midline (15 cases) and glioblastoma RTK/mesenchymal (seven cases). Two cases clustered with ANA_PA, four cases with LGG classes and one with GBM_MYCN. Only fifteen cases reached a calibrated score >0.84 when the cases were uploaded to DKFZ Classifier. GBM_midline‐clustered tumours had a poorer overall survival (OS) compared with the PXA‐clustered tumours (p = 0.030). LGG‐clustered cases had a significantly better survival than GBM_midline‐clustered tumours and glioblastoma RTK/mesenchymal‐clustered tumours. Only 13/21 (62%) of PXA‐clustered cases were BRAF V600E mutated. Most GBM_midline‐clustered cases were not located in the midline. GBM_midline‐clustered cases were characterised by PDGFRA amplification/mutation (73.3%), mutations of mismatch repair genes (40.0%), and all showed H3K27me3 and EZH1P loss, and an unmethylated MGMT promoter. Across the whole cohort, MGMT promoter methylation and wt TERT promoter were favourable prognosticators. Mismatch repair gene mutations were poor prognosticators and together with methylation class and MGMT methylation, maintained their significance in multivariate analyses. BRAF mutation was a good prognosticator in the PXA‐clustered tumours. Conclusion Methylation profiling is a useful tool in the diagnosis and prognostication of AYA glioblastomas, and the methylation classes have distinct molecular characteristics. The usual molecular diagnostic criteria for adult IDHwt glioblastoma should be applied with caution within the AYA age group.

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Section: Discussionmentioning

confidence: 70%

Molecular landscape of IDH‐wild‐type, H3‐wild‐type glioblastomas of adolescents and young adults

Shi

Huang

et al. 2022

Neuropathology Appl Neurobio

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“…The histopathological evaluation was made in accordance with the WHO criteria valid at the time of surgery and reclassified according to the WHO classification of 2021. Molecular analysis of IDH -mutation, 1p/19q codeletion, and homozygous deletion of CDKN2A/B were performed as previously described ( 22 ). Immunohistochemistry on formalin-fixed paraffin-embedded sections with antibodies against Ki67 to detect the fraction of proliferating cells in the tumor was performed as described earlier ( 23 ).…”

Section: Methodsmentioning

confidence: 99%

WHO Grade Loses Its Prognostic Value in Molecularly Defined Diffuse Lower-Grade Gliomas

et al. 2022

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BackgroundWhile molecular insights to diffuse lower-grade glioma (dLGG) have improved the basis for prognostication, most established clinical prognostic factors come from the pre-molecular era. For instance, WHO grade as a predictor for survival in dLGG with isocitrate dehydrogenase (IDH) mutation has recently been questioned. We studied the prognostic role of WHO grade in molecularly defined subgroups and evaluated earlier used prognostic factors in the current molecular setting.Material and MethodsA total of 253 adults with morphological dLGG, consecutively included between 2007 and 2018, were assessed. IDH mutations, codeletion of chromosomal arms 1p/19q, and cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions were analyzed.ResultsThere was no survival benefit for patients with WHO grade 2 over grade 3 IDH-mut dLGG after exclusion of tumors with known CDKN2A/B homozygous deletion (n=157) (log-rank p=0.97). This was true also after stratification for oncological postoperative treatment and when astrocytomas and oligodendrogliomas were analyzed separately. In IDH-mut astrocytomas, residual tumor volume after surgery was an independent prognostic factor for survival (HR 1.02; 95% CI 1.01–1.03; p=0.003), but not in oligodendrogliomas (HR 1.02; 95% CI 1.00–1.03; p=0.15). Preoperative tumor size was an independent predictor in both astrocytomas (HR 1.03; 95% CI 1.00–1.05; p=0.02) and oligodendrogliomas (HR 1.05; 95% CI 1.01–1.09; p=0.01). Age was not a significant prognostic factor in multivariable analyses (astrocytomas p=0.64, oligodendrogliomas p=0.08).ConclusionOur findings suggest that WHO grade is not a robust prognostic factor in molecularly well-defined dLGG. Preoperative tumor size remained a prognostic factor in both IDH-mut astrocytomas and oligodendrogliomas in our cohort, whereas residual tumor volume predicted prognosis in IDH-mut astrocytomas only. The age cutoffs for determining high risk in patients with IDH-mut dLGG from the pre-molecular era are not supported by our results.

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“…Tumors that were previously classified according to WHO 2007 were reclassified according to the WHO 2016 criteria for the purpose of the study. Reclassification according to the WHO 2016 CNS classification system, based on IDH mutation and 1p/19q codeletion status, was performed as previously described by Ferreyra Vega et al 38 The new classification system from 2021 did not change the nomenclature further. 39 …”

Section: Methodsmentioning

confidence: 99%

Stemness and clinical features in relation to the subventricular zone in diffuse lower-grade glioma: an exploratory study

Corell

Vecchio

Vega

et al. 2022

Neuro-Oncology Advances

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Background The subventricular zone (SVZ) of the human brain is a site of adult stem cell proliferation and a microenvironment for neural stem cells (NSCs). It has been suggested that NSCs in the SVZ are potential cells of origin containing driver mutations of glioblastoma, but their role in the origin of diffuse lower-grade gliomas (dLGG) is not much studied. Methods We included 188 patients ≥18 years with IDH-mutated dLGG (WHO grade 2–3) histologically diagnosed between 2007–2020. Tissue microarrays of tumor samples for patients between 2007–2016 were used for immunodetection of Nestin, SOX2, SOX9, KLF4, NANOG, CD133 cMYC and Ki67. DNA methylation profile was used for stemness index (mDNAsi). Tumor contact with the SVZ was assessed and the distance was computed. Results Overall, 70.2% of the dLGG had SVZ contact. Tumors with SVZ contact were larger (102.4 vs. 30.9 ml, p<0.01), the patients were older (44.3 vs. 40.4 years, p=0.04) and more often had symptoms related to increased intracranial pressure (ICP) (31.8% vs. 7.1%, p<0.01). The expression of SOX2, SOX9, Nestin and Ki67 showed inter-sample variability, but no difference was found between tumors with or without SVZ contact, nor with the actual distance to the SVZ. mDNAsi was similar between groups (p=0.42). Conclusion We found no statistical relationship between proximity with the SVZ and mDNAsi or expression of SOX2, SOX9, Nestin and Ki67 in IDH-mutated dLGG. Our data suggests that the potential impact of SVZ on IDH-mutated dLGG is probably not associated with a more stemness-like tumor profile.

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DNA methylation profiling for molecular classification of adult diffuse lower-grade gliomas

Cited by 30 publications

References 39 publications

Molecular landscape of IDH‐wild‐type, H3‐wild‐type glioblastomas of adolescents and young adults

Molecular landscape of IDH‐wild‐type, H3‐wild‐type glioblastomas of adolescents and young adults

WHO Grade Loses Its Prognostic Value in Molecularly Defined Diffuse Lower-Grade Gliomas

Stemness and clinical features in relation to the subventricular zone in diffuse lower-grade glioma: an exploratory study

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