IDH mutation-specific radiomic signature in lower-grade gliomas.
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ABSTRACT:
SUBMITTER: Liu X
PROVIDER: S-EPMC6366985 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Mutations in isocitrate dehydrogenase (IDH) affect the development and prognosis of gliomas. We investigated the role of IDH mutations in the regulation of immune phenotype in lower-grade gliomas (LGGs).Method and patients: A total of 1,008 cases with clinical and IDH mutation data from five cohorts were enrolled. Samples with RNA sequencing data from the Chinese Glioma Genome Atlas (CGGA) were used as training set, whereas RNA data from the Cancer Genome Atlas, Repository for Molecular Brain Neoplasia, GSE16011, and CGGA microarray databases were used for validation. R language tools and bioinformatics analysis were used for gene signature construction and biological function annotation.Results: We found that IDH mutations caused down-regulation of local immune response as among 332 immune system-related genes, 196(59.0%) were differentially expressed according to IDH mutation status. Nearly 70% of those differentially expressed genes exhibited prognostic value in LGGs. An immune response-based gene signature was constructed that distinguished cases with high- or low-risk of unfavorable prognosis and remained an independent prognostic factor in multivariate analyses in both training and validation cohorts. Samples from high-risk cases exhibited elevated expression of genes involved in immune response and NF-?B pathway activation. Furthermore, we found a strong correlation between the risk score and T cells, macrophage-related immune response, and expression of several prominent immune checkpoints.Conclusion: Our results indicated that mutant IDH is highly associated with the regulation of the immune microenvironment in LGGs. The observed immune system gene signature, which was sensitive to IDH mutation status, efficiently predicted patient survival.
| S-EPMC5980422 | biostudies-literature
Project description:ObjectiveWe aimed to identify a radiomic signature to be used as a noninvasive biomarker of prognosis in patients with lower-grade gliomas (LGGs) and to reveal underlying biological processes through comprehensive radiogenomic investigation.MethodsWe extracted 55 radiomic features from T2-weighted images of 233 patients with LGGs (training cohort: n = 85; validation cohort: n = 148). Univariate Cox regression and linear risk score formula were applied to generate a radiomic-based signature. Gene ontology analysis of highly expressed genes in the high-risk score group was conducted to establish a radiogenomic map. A nomogram was constructed for individualized survival prediction.ResultsThe six-feature radiomic signature stratified patients in the training cohort into low- or high-risk groups for overall survival (P = 0.0018). This result was successfully verified in the validation cohort (P = 0.0396). Radiogenomic analysis revealed that the prognostic radiomic signature was associated with hypoxia, angiogenesis, apoptosis, and cell proliferation. The nomogram resulted in high prognostic accuracy (C-index: 0.92, C-index: 0.70) and favorable calibration for individualized survival prediction in the training and validation cohorts.ConclusionsOur results suggest a great potential for the use of radiomic signature as a biological surrogate in providing prognostic information for patients with LGGs.
| S-EPMC6224242 | biostudies-literature
Project description:Background:Vascular gene expression patterns in lower-grade gliomas (LGGs; diffuse World Health Organization [WHO] grades II-III gliomas) have not been thoroughly investigated. The aim of this study was to molecularly characterize LGG vessels and determine if tumor isocitrate dehydrogenase (IDH) mutation status affects vascular phenotype. Methods:Gene expression was analyzed using an in-house dataset derived from microdissected vessels and total tumor samples from human glioma in combination with expression data from 289 LGG samples available in the database of The Cancer Genome Atlas. Vascular protein expression was examined by immunohistochemistry in human brain tumor tissue microarrays (TMAs) representing WHO grades II-IV gliomas and nonmalignant brain samples. Regulation of gene expression was examined in primary endothelial cells in vitro. Results:Gene expression analysis of WHO grade II glioma indicated an intermediate stage of vascular abnormality, less severe than that of glioblastoma vessels but distinct from normal vessels. Enhanced expression of laminin subunit alpha 4 (LAMA4) and angiopoietin 2 (ANGPT2) in WHO grade II glioma was confirmed by staining of human TMAs. IDH wild-type LGGs displayed a specific angiogenic gene expression signature, including upregulation of ANGPT2 and serpin family H (SERPINH1), connected to enhanced endothelial cell migration and matrix remodeling. Transcription factor analysis indicated increased transforming growth factor beta (TGFβ) and hypoxia signaling in IDH wild-type LGGs. A subset of genes specifically induced in IDH wild-type LGG vessels was upregulated by stimulation of endothelial cells with TGFβ2, vascular endothelial growth factor, or cobalt chloride in vitro. Conclusion:IDH wild-type LGG vessels are molecularly distinct from the vasculature of IDH-mutated LGGs. TGFβ and hypoxia-related signaling pathways may be potential targets for anti-angiogenic therapy of IDH wild-type LGG.
| S-EPMC6176806 | biostudies-other
Project description:BackgroundMany low-grade gliomas (LGG) harbor isocitrate dehydrogenase (IDH) mutations. Although IDH mutation is known to be epileptogenic, the rate of refractory seizures in LGG with IDH mutation vs wild-type had not been previously compared. We therefore compared seizure pharmacoresistance in IDH-mutated and wild-type LGGs.MethodsSingle-institution retrospective study of patients with histologic proven LGG, known IDH mutation status, seizures, and ≥2 neurology clinic encounters. Seizure history was followed until histological high-grade transformation or death. Seizures requiring ≥2 changes in anti-epileptic drugs were considered pharmacoresistant. Incidence rates of pharmacoresistant seizures were estimated using competing risks methodology.ResultsOf 135 patients, 25 patients (19%) had LGGs classified as IDH wild-type. Of those with IDH mutation, 104 (94.5%) were IDH1 R132H; only 6 were IDH2 R172K. 120 patients (89%) had tumor resection, and 14 (10%) had biopsy. Initial post-surgical management included observation (64%), concurrent chemoradiation (23%), chemotherapy alone (9%), and radiotherapy alone (4%). Seizures became pharmacoresistant in 24 IDH-mutated patients (22%) and in 3 IDH wild-type patients (12%). The 4-year cumulative incidence of intractable seizures was 17.6% (95% CI: 10.6%-25.9%) in IDH-mutated and 11% (95% CI: 1.3%-32.6%) in IDH wild-type LGG (Gray's P-value = .26).Conclusions22% of the IDH-mutated patients developed pharmacoresistant seizures, compared to 12% of the IDH wild-type tumors. The likelihood of developing pharmacoresistant seizures in patients with LGG-related epilepsy is independent to IDH mutation status, however, IDH-mutated tumors were approximately twice as likely to experience LGG-related pharmacoresistant seizures.
| S-EPMC8557671 | biostudies-literature
Project description:We developed end-to-end deep learning models using whole slide images of adults diagnosed with diffusely infiltrating, World Health Organization (WHO) grade 2 gliomas to predict prognosis and the mutation status of a somatic biomarker, isocitrate dehydrogenase (IDH) 1/2. The models, which utilize ResNet-18 as a backbone, were developed and validated on 296 patients from The Cancer Genome Atlas (TCGA) database. To account for the small sample size, repeated random train/test splits were performed for hyperparameter tuning, and the out-of-sample predictions were pooled for evaluation. Our models achieved a concordance- (C-) index of 0.715 (95% CI: 0.569, 0.830) for predicting prognosis and an area under the curve (AUC) of 0.667 (0.532, 0.784) for predicting IDH mutations. When combined with additional clinical information, the performance metrics increased to 0.784 (95% CI: 0.655, 0.880) and 0.739 (95% CI: 0.613, 0.856), respectively. When evaluated on the WHO grade 3 gliomas from the TCGA dataset, which were not used for training, our models predicted survival with a C-index of 0.654 (95% CI: 0.537, 0.768) and IDH mutations with an AUC of 0.814 (95% CI: 0.721, 0.897). If validated in a prospective study, our method could potentially assist clinicians in managing and treating patients with diffusely infiltrating gliomas.
| S-EPMC8377095 | 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:ObjectiveThe aim of this study was to develop a radiomics signature for prediction of progression-free survival (PFS) in lower-grade gliomas and to investigate the genetic background behind the radiomics signature.MethodsIn this retrospective study, training (n?=?216) and validation (n?=?84) cohorts were collected from the Chinese Glioma Genome Atlas and the Cancer Genome Atlas, respectively. For each patient, a total of 431 radiomics features were extracted from preoperative T2-weighted magnetic resonance images. A radiomics signature was generated in the training cohort, and its prognostic value was evaluated in both the training and validation cohorts. The genetic characteristics of the group with high-risk scores were identified by radiogenomic analysis, and a nomogram was established for prediction of PFS.ResultsThere was a significant association between the radiomics signature (including 9 screened radiomics features) and PFS, which was independent of other clinicopathologic factors in both the training (P?<?0.001, multivariable Cox regression) and validation (P?=?0.045, multivariable Cox regression) cohorts. Radiogenomic analysis revealed that the radiomics signature was associated with the immune response, programmed cell death, cell proliferation, and vasculature development. A nomogram established using the radiomics signature and clinicopathologic risk factors demonstrated high accuracy and good calibration for prediction of PFS in both the training (C-index, 0.684) and validation (C-index, 0.823) cohorts.ConclusionsPFS can be predicted non-invasively in patients with LGGs by a group of radiomics features that could reflect the biological processes of these tumors.
| S-EPMC6202688 | biostudies-literature
Project description:We studied if combination genetic signature potentially stratifies lower-grade gliomas better than histology by investigating 214 lower-grade gliomas for IDH1/2 and TERTp mutations, 1p/19q codeletion and EGFR amplification as to their impact on prognostication. Prognostic association of grading was independent of other prognostic variables including age, histological type, IDH1/2, 1p/19q and TERTp status. No single marker, including IDH1/2, superseded grading in prognostication, indicating grading was still a very important tool. Prognosis was most favorable in 31.7% of patients with IDH1/2 mutation and either 1p/19q codeletion or TERTp mutation (IDHmut-OT), intermediate in 45.8% of patients with IDH1/2 mutation only (IDHmut) and 16.9% of patients without any of the alterations (IDHwt), and poorest in 5.6% of patients with wild-type IDH1/2 and either TERTp mutation or EGFR amplification (IDHwt-ET). Our results suggested not all IDH1/2 wild-type lower-grade gliomas are aggressive and additional biomarkers are required to identify glioblastoma-equivalent tumors. Multivariate analysis revealed independent prognostic values of grading and genetic signature. Grade II IDHwt-ET gliomas exhibited shorter survival than IDH1/2 mutated grade III gliomas, suggesting combination genetic signature potentially superseded grading in prognostication. In summary, biomarker-based stratification is useful in the diagnosis and prognostication of lower-grade gliomas, and should be used together with grading.
| S-EPMC4673237 | biostudies-literature
Project description:BackgroundIsocitrate dehydrogenase (IDH) wildtype (wt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined.MethodsWe searched retrospectively all patients diagnosed with diffuse World Health Organization (WHO) grades II and III gliomas at our center (1989-2020).ResultsOut of 517 grade II gliomas, 47 were "diffuse astrocytomas, IDHwt." Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found telomerase reverse transcriptase (TERT) promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%), but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs 19 mo for IDHwt grade III gliomas) (P < 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update 3. Median OS in this subset was 42 months, which was shorter compared with patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 mo), but substantially longer compared with IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 mo, P < 0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 mo). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%).ConclusionsOur findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.
| S-EPMC8168809 | biostudies-literature
Project description:Glioma is the most common malignant tumor in the central nervous system (CNS). Lower-grade gliomas (LGG) refer to Grade II and III gliomas. In LGG patients, seizure often appears as an initial symptom and play an important role in clinical performance and quality of life of the patients. To date, the relationship between the onset of seizures and the molecular pathology in gliomas is still poorly investigated. In this study, we investigate the potential relationship between isocitrate dehydrogenase (IDH)/telomerase reverse transcriptase promoter (TERTp) mutations and preoperative seizures in patients with LGG. 289 adult LGG patients were enrolled in this study. Data of clinical characteristics and molecular pathology were acquired. Sanger sequencing was used to detect IDH/TERTp mutations. Chi-square test was performed to determine if the IDH/TERTp mutations were associated with seizures and seizure types. In 289 LGG patients, preoperative seizures accounted for 25.3% (73/289), IDH mutations accounted for 34.3%(99/289), and TERTp mutations accounted for 44.3% (128/289). The correlation analysis demonstrated that IDH mutation is a significant factor influencing the occurrence of tumor-related epilepsy (P?<.001, chi-square test). On the other hand, the statistical analysis revealed no significant correlation between TERTp mutations and seizure in LGG patients (P?=?.102, chi-square test). The tumor-related epilepsy rates vary among different subgroups according to IDH/TERTp mutations. However, there is no definite correlation between the IDH (P?=?1.000, chi-square test)/TERTp (P?=?.613, chi-square test) mutations and the types of epileptic seizure. IDH mutations are more common in preoperative LGG patients with epileptic symptoms, suggesting that this mutation is positively correlated with seizures. However, there was no significant correlation between TERTp mutations and seizures. Different molecular pathologic types based on IDH/TERTp have different incidences of tumor-associated epilepsy in LGGs.
| S-EPMC6320119 | biostudies-literature