Heterogeneity matching and IDH prediction in adult-type diffuse gliomas: a DKI-based habitat analysis
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ABSTRACT:
SUBMITTER: Liu Y
PROVIDER: S-EPMC10713834 | biostudies-literature | 2023 Jan
REPOSITORIES: biostudies-literature
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Project description:BackgroundIntratumor heterogeneity (ITH) is a key biological characteristic of gliomas. This study aimed to characterize ITH in adult-type diffuse gliomas and assess the feasibility of using habitat imaging based on dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and diffusion-weighted imaging (DWI) to preoperatively predict isocitrate dehydrogenase (IDH) genotypes and prognosis.MethodsSixty-three adult-type diffuse gliomas with known IDH genotypes were enrolled. Volume transfer constant (Ktrans) and apparent diffusion coefficient (ADC) maps were acquired from DCE-MRI and DWI, respectively. After tumor segmentation, the k-means algorithm clustered Ktrans and ADC image voxels to generate spatial habitats and extract quantitative image features. Receiver operating characteristic (ROC) curves and area under the curve (AUC) were used to evaluate IDH predictive performance. Multivariable logistic regression models were constructed and validated using leave-one-out cross-validation, and the contrast-enhanced subgroup was analyzed independently. Kaplan-Meier and Cox proportional hazards regression analyses were used to investigate the relationship between tumor habitats and progression-free survival (PFS) in the two IDH groups.ResultsThree habitats were identified: Habitat 1 (hypo-vasopermeability and hyper-cellularity), Habitat 2 (hypo-vasopermeability and hypo-cellularity), and Habitat 3 (hyper-vasopermeability). Compared to the IDH wild-type group, the IDH mutant group exhibited lower mean Ktrans values in Habitats 1 and 2 (both P < 0.001), higher volume (P < 0.05) and volume percentage (pVol, P < 0.01) of Habitat 2, and lower volume and pVol of Habitat 3 (both P < 0.001). The optimal logistic regression model for IDH prediction yielded an AUC of 0.940 (95% confidence interval [CI]: 0.880-1.000), which improved to 0.948 (95% CI: 0.890-1.000) after cross-validation. Habitat 2 contributed the most to the model, consistent with the findings in the contrast-enhanced subgroup. In IDH wild-type group, pVol of Habitat 2 was identified as a significant risk factor for PFS (high- vs. low-pVol subgroup, hazard ratio = 2.204, 95% CI: 1.061-4.580, P = 0.034), with a value below 0.26 indicating a 5-month median survival benefit.ConclusionsHabitat imaging employing DCE-MRI and DWI may facilitate the characterization of ITH in adult-type diffuse gliomas and serve as a valuable adjunct in the preoperative prediction of IDH genotypes and prognosis.Clinical trial numberNot applicable.
| S-EPMC11807326 | biostudies-literature
Project description:ObjectiveHigh-risk types of diffuse gliomas in adults include isocitrate dehydrogenase (IDH) wild-type glioblastomas and grade 4 astrocytomas. Achieving noninvasive prediction of high-risk molecular subtypes of gliomas is important for personalized and precise diagnosis and treatment.MethodsWe retrospectively collected data from 116 patients diagnosed with adult diffuse gliomas. Multiple high-risk molecular markers were tested, and various habitat models and whole-tumor models were constructed based on preoperative routine and diffusion kurtosis imaging (DKI) sequences to predict high-risk molecular subtypes of gliomas. Feature selection and model construction utilized Least absolute shrinkage and selection operator (LASSO) and support vector machine (SVM). Finally, the Wilcoxon rank-sum test was employed to explore the correlation between habitat quantitative features (intra-tumor heterogeneity score，ITH score) and heterogeneity, as well as high-risk molecular subtypes.ResultsThe results showed that the habitat analysis model based on DKI performed remarkably well (with AUC values reaching 0.977 and 0.902 in the training and test sets, respectively). The model's performance was further enhanced when combined with clinical variables. (The AUC values were 0.994 and 0.920, respectively.) Additionally, we found a close correlation between ITH score and heterogeneity, with statistically significant differences observed between high-risk and non-high-risk molecular subtypes.InterpretationThe habitat model based on DKI is an ideal means for preoperatively predicting high-risk molecular subtypes of gliomas, holding significant value for noninvasively alerting malignant gliomas and those with malignant transformation potential.
| S-EPMC11330218 | biostudies-literature
Project description:Diffuse gliomas are among the most common adult central nervous system tumors with an annual incidence of more than 16,000 cases in the United States. Until very recently, the diagnosis of these tumors was based solely on morphologic features, however, with the publication of the WHO Classification of Tumours of the Central Nervous System, revised 4th edition in 2016, certain molecular features are now included in the official diagnostic and grading system. One of the most significant of these changes has been the division of adult astrocytomas into IDH-wildtype and IDH-mutant categories in addition to histologic grade as part of the main-line diagnosis, although a great deal of heterogeneity in the clinical outcome still remains to be explained within these categories. Since then, numerous groups have been working to identify additional biomarkers and prognostic factors in diffuse gliomas to help further stratify these tumors in hopes of producing a more complete grading system, as well as understanding the underlying biology that results in differing outcomes. The field of neuro-oncology is currently in the midst of a "molecular revolution" in which increasing emphasis is being placed on genetic and epigenetic features driving current diagnostic, prognostic, and predictive considerations. In this review, we focus on recent advances in adult diffuse glioma biomarkers and prognostic factors and summarize the state of the field.
| S-EPMC7408495 | biostudies-literature
Project description:Multiple metabolic pathways are utilized to maintain cellular homeostasis. Given the evidence that altered cell metabolism significantly contributes to glioma biology, the current research efforts aim to improve our understanding of metabolic rewiring between glioma's complex genotype and tissue context. In addition, extensive molecular profiling has revealed activated oncogenes and inactivated tumor suppressors that directly or indirectly impact the cellular metabolism that is associated with the pathogenesis of gliomas. The mutation status of isocitrate dehydrogenases (IDHs) is one of the most important prognostic factors in adult-type diffuse gliomas. This review presents an overview of the metabolic alterations in IDH-mutant gliomas and IDH-wildtype glioblastoma (GBM). A particular focus is placed on targeting metabolic vulnerabilities to identify new therapeutic strategies for glioma.
| S-EPMC10138713 | biostudies-literature
Project description:Diffuse gliomas are the most prevalent malignant primary brain tumors in adults and remain incurable despite standard therapy. Tumor recurrence is currently inevitable, which contributes to a persistent high morbidity and mortality in these patients. In this study, we examined the genome-wide DNA methylation profiles of primary and recurrent adult-type IDH-mutant gliomas to elucidate DNA methylation changes associated with tumor progression (with or without malignant transformation). We analyzed DNA methylation profiles of 37 primary IDH-mutant gliomas and 42 paired recurrences using the DNA methylation EPIC beadChip array. DNA methylation-based classification reflected the tumor progression over time. We observed a methylation subtype switch in a proportion of IDH-mutant astrocytomas; the primary tumors were subclassified as low-grade astrocytomas, which progressed to high-grade astrocytomas in the recurrent tumors. The CNS WHO grade 4 IDH-mutant astrocytomas did not always resemble methylation subclasses of higher grades. The number of differentially methylated CpG sites increased over time, and astrocytomas accumulated more differentially methylated CpG sites than oligodendrogliomas during tumor progression. Few differentially methylated CpG sites were shared between patients. We demonstrated that DNA methylation profiles are mostly maintained during IDH-mutant glioma progression, but CpG site-specific methylation alterations can occur.
| S-EPMC9899392 | biostudies-literature
Project description:BackgroundAstrocytoma of the isocitrate dehydrogenase (IDH) wild-type gene is described as a provisional entity within the new World Health Organization (WHO) classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be substratified prognostically.MethodsSeven hundred and eighteen adult WHO grades II and III patients with gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. One hundred and sixty-six patients with IDH wild-type cases were identified for further studies, and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter (TERTp), and BRAF were examined.ResultsEGFR amplification, BRAF, and H3F3A mutations were observed in 13.8%, 6.9%, and 9.5% of patients, respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.8% of cases. Favorable outcome was observed in patients with young age, oligodendroglial phenotype, and grade II histology. Independent adverse prognostic values of older age, nontotal resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariable analysis. Tumors were further classified into "molecularly" high grade (harboring EGFR, H3F3A, or TERTp) (median overall survival = 1.23 y) and lower grade (lacking all of the 3) (median overall survival = 7.63 y) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification.ConclusionAdult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers, including MYB, EGFR, TERTp, and H3F3A, should be examined to delineate discrete favorable and unfavorable prognostic groups.
| S-EPMC5596181 | biostudies-literature
Project description:Molecular subtyping and grading of adult-type diffuse gliomas are essential for treatment decisions and patient prognosis. We introduce GlioMT, an interpretable multimodal transformer that integrates imaging and clinical data to predict the molecular subtype and grade of adult-type diffuse gliomas according to the 2021 WHO classification. GlioMT is trained on multiparametric MRI data from an institutional set of 1053 patients with adult-type diffuse gliomas to predict the IDH mutation status, 1p/19q codeletion status, and tumor grade. External validation on the TCGA (200 patients) and UCSF (477 patients) shows that GlioMT outperforms conventional CNNs and visual transformers, achieving AUCs of 0.915 (TCGA) and 0.981 (UCSF) for IDH mutation, 0.854 (TCGA) and 0.806 (UCSF) for 1p/19q codeletion, and 0.862 (TCGA) and 0.960 (UCSF) for grade prediction. GlioMT enhances the reliability of clinical decision-making by offering interpretability through attention maps and contributions of imaging and clinical data.
| S-EPMC11883078 | biostudies-literature
Project description:Adult-type diffuse gliomas comprise IDH-mutant astrocytomas, IDH-mutant 1p/19q codeleted oligodendrogliomas (ODG), and IDH-wildtype glioblastomas (GBM). GBM display genome instability, which may result from two genetic events leading to massive chromosome alterations: chromothripsis (CT) and whole-genome duplication (WGD). The better prognosis of the latter may be related to their genome stability compared to GBM. Pangenomic profiles of 297 adult diffuse gliomas were analyzed at initial diagnosis using SNP arrays, including 192 GBM and 105 IDH-mutant gliomas (61 astrocytomas and 44 ODG). Tumor ploidy was assessed with Genome Alteration Print and CT events with CTLPScanner and through manual screening.
2024-12-24 | E-MTAB-13542 | biostudies-arrayexpress
Project description:High-grade adult-type diffuse gliomas are malignant neuroepithelial tumors with poor survival rates in combined chemoradiotherapy. The current WHO classification is based on IDH1/2 mutational and 1p/19q codeletion status. Glioma proteome alterations remain undercharacterized despite their promise for a better molecular patient stratification and therapeutic target identification. Here, we use mass spectrometry to characterize 42 formalin-fixed, paraffin-embedded (FFPE) samples from IDH-wild-type (IDHwt) gliomas, IDH-mutant (IDHmut) gliomas with and without 1p/19q codeletion, and non-neoplastic controls. Based on more than 5,500 quantified proteins and 5,000 phosphosites, gliomas separate by IDH1/2 mutational status but not by 1p/19q status. Instead, IDHmut gliomas split into two proteomic subtypes with widespread perturbations, including aerobic/anaerobic energy metabolism. Validations with three independent glioma proteome datasets confirm these subgroups and link the IDHmut subtypes to the established proneural and classic/mesenchymal subtypes in IDHwt glioma. This demonstrates common phenotypic subtypes across the IDH status with potential therapeutic implications for patients with IDHmut gliomas.
| S-EPMC9873829 | biostudies-literature
Project description:Gene fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets. Using RNA-sequencing, we interrogated a large cohort of gliomas to assess for the incidence of targetable genetic fusions. Gliomas (n = 390) were profiled using the ArcherDx FusionPlex Assay. Fifty-two gene targets were analyzed and fusions with preserved kinase domains were investigated. Overall, 36 gliomas (9%) harbored a total of 37 potentially targetable fusions, the majority of which were found in astrocytomas (n = 34). Within this lineage 11% (25/235) of glioblastomas, 12% (5/42) of anaplastic astrocytomas, 8% (2/25) of grade II astrocytomas, and 33% (2/6) of pilocytic astrocytoma harbored targetable fusions. Fusions were significantly more frequent in IDH wild-type tumors (12%, n = 31/261) relative to IDH mutants (4%; n = 4/109) (p = 0.011). No fusions were seen in oligodendrogliomas. The most frequently observed therapeutically targetable fusions were in FGFR (n = 12), MET (n = 11), and NTRK (n = 8). Several additional novel fusions that have not been previously described in gliomas were identified including EGFR:VWC2 and FGFR3:NBR1. In summary, targetable gene fusions are enriched in IDH wild-type high-grade astrocytic tumors, which will influence enrollment in and interpretation of clinical trials of glioma patients.
| S-EPMC5961205 | biostudies-literature