CIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas.
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ABSTRACT:
SUBMITTER: Brat DJ
PROVIDER: S-EPMC8443062 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:IDH-mutant astrocytomas are significantly less aggressive than their IDH-wildtype counterparts. We analyzed The Cancer Genome Atlas dataset (TCGA) and identified a small group of IDH-mutant, WHO grade II-III astrocytomas (n = 14) with an unexpectedly poor prognosis characterized by a rapid progression to glioblastoma and death within 3 years of the initial diagnosis. Compared with IDH-mutant tumors with the typical, extended progression-free survival in a control group of age-similar patients, the tumors in the rapidly progressing group were characterized by a markedly increased level of overall copy number alterations ([CNA]; p = 0.006). In contrast, the mutation load was similar, as was the methylation pattern, being consistent with IDH-mutant astrocytoma. Two of the gliomas (14%) in the rapidly progressing, IDH-mutant group but none of the other grade II-III gliomas in the TCGA (n = 283) had pathogenic mutations in genes (FANCB and APC) associated with maintaining chromosomal stability. These results suggest that chromosomal instability can negate the beneficial effect of IDH mutations in WHO II-III astrocytomas. The mechanism of the increased CNA is unknown but in some cases appears to be due to mutations in genes with a role in chromosomal stability. Increased CNA could serve as a biomarker for tumors at risk for rapid progression.
| S-EPMC6005148 | biostudies-literature
Project description:Diffusely infiltrating gliomas are among the most common central nervous system tumors in adults. Over the past decade, the subcategorization of these tumors has changed to include both traditional histologic features and more recently identified molecular factors. However, one molecular feature that has yet to be integrated is the presence/absence of chromosomal instability (CIN). Herein, we use global methylation profiling to evaluate a reference cohort of IDH-mutant astrocytomas with and without prior evidence of CIN (n = 42), and apply the resulting methylation-based characteristics to a larger test cohort of publicly-available IDH-mutant astrocytomas (n = 245). We demonstrate that IDH-mutant astrocytomas with evidence of CIN cluster separately from their chromosomally-stable counterparts. CIN cases were associated with higher initial histologic grade, altered expression patterns of genes related to CIN in other cancers, elevated initial total copy number burden, and significantly worse progression-free and overall survival. In addition, in a grade-for-grade analysis, patients with CIN-positive WHO grade 2 and 3 tumors had significantly worse survival. These results suggest that global methylation profiling can be used to discriminate between chromosomally stable and unstable IDH-mutant astrocytomas, and may therefore provide a reliable and cost-effective method for identifying gliomas with chromosomal instability and resultant poor clinical outcome.
| S-EPMC8908645 | biostudies-literature
Project description:The 2021 WHO Classification of Central Nervous System Tumors recommended evaluation of cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion in addition to codeletion of 1p/19q to characterize IDH-mutant gliomas. Here, we demonstrated the use of a nanopore-based copy-number variation sequencing (nCNV-seq) approach to simultaneously identify deletions of CDKN2A/B and 1p/19q. The nCNV-seq approach was initially evaluated on three distinct glioma cell lines and then applied to 19 IDH-mutant gliomas (8 astrocytomas and 11 oligodendrogliomas) from patients. The whole-arm 1p/19q codeletion was detected in all oligodendrogliomas with high concordance among nCNV-seq, FISH, DNA methylation profiling, and whole-genome sequencing. For the CDKN2A/B deletion, nCNV-seq detected the loss in both astrocytoma and oligodendroglioma, with strong correlation with the CNV profiles derived from whole-genome sequencing (Pearson correlation (r) = 0.95, P < 2.2 × 10-16 to r = 0.99, P < 2.2 × 10-16 ) and methylome profiling. Furthermore, nCNV-seq can differentiate between homozygous and hemizygous deletions of CDKN2A/B. Taken together, nCNV-seq holds promise as a new, alternative approach for a rapid and simultaneous detection of the molecular signatures of IDH-mutant gliomas without capital expenditure for a sequencer.
| S-EPMC10711254 | biostudies-literature
Project description:This study aimed to investigate the potential of quantitative radiomic data extracted from conventional MR images in discriminating IDH-mutant grade 4 astrocytomas from IDH-wild-type glioblastomas (GBMs). A cohort of 57 treatment-naïve patients with IDH-mutant grade 4 astrocytomas (n = 23) and IDH-wild-type GBMs (n = 34) underwent anatomical imaging on a 3T MR system with standard parameters. Post-contrast T1-weighted and T2-FLAIR images were co-registered. A semi-automatic segmentation approach was used to generate regions of interest (ROIs) from different tissue components of neoplasms. A total of 1050 radiomic features were extracted from each image. The data were split randomly into training and testing sets. A deep learning-based data augmentation method (CTGAN) was implemented to synthesize 200 datasets from the training sets. A total of 18 classifiers were used to distinguish two genotypes of grade 4 astrocytomas. From generated data using 80% training set, the best discriminatory power was obtained from core tumor regions overlaid on post-contrast T1 using the K-best feature selection algorithm and a Gaussian naïve Bayes classifier (AUC = 0.93, accuracy = 0.92, sensitivity = 1, specificity = 0.86, PR_AUC = 0.92). Similarly, high diagnostic performances were obtained from original and generated data using 50% and 30% training sets. Our findings suggest that conventional MR imaging-based radiomic features combined with machine/deep learning methods may be valuable in discriminating IDH-mutant grade 4 astrocytomas from IDH-wild-type GBMs.
| S-EPMC9913426 | biostudies-literature
Project description:AbstractThe T2-FLAIR (fluid attenuated inversion recovery) mismatch sign is an easily detectable imaging sign on routine clinical MRI studies that suggests diagnosis of isocitrate dehydrogenase (IDH)-mutant 1p/19q non-codeleted gliomas. Multiple independent studies show that the T2-FLAIR mismatch sign has near-perfect specificity, but low sensitivity for diagnosing IDH-mutant astrocytomas. Thus, the T2-FLAIR mismatch sign represents a non-invasive radiogenomic diagnostic finding with potential clinical impact. Recently, false positive cases have been reported, many related to variable application of the sign's imaging criteria and differences in image acquisition, as well as to differences in the included patient populations. Here we summarize the imaging criteria for the T2-FLAIR mismatch sign, review similarities and differences between the multiple validation studies, outline strategies to optimize its clinical use, and discuss potential opportunities to refine imaging criteria in order to maximize its impact in glioma diagnostics.
| S-EPMC7339896 | biostudies-literature
Project description:BackgroundThe T2-FLAIR mismatch sign (T2FM) has nearly 100% specificity for predicting IDH-mutant and 1p/19q noncodeleted astrocytomas (astrocytomas). However, only 18.2%-56.0% of astrocytomas demonstrate a positive T2FM. Methods must be considered for distinguishing astrocytomas from negative T2FM gliomas. In this study, positive T2FM gliomas were manually distinguished from nonenhancing gliomas, and then a support vector machine (SVM) classification model was used to distinguish astrocytomas from negative T2FM gliomas.MethodsNonenhancing gliomas (regardless of pathological type or grade) diagnosed between January 2022 and October 2022 (N = 300) and November 2022 and March 2023 (N = 196) will comprise the training and validation sets, respectively. Our method for distinguishing astrocytomas from nonenhancing gliomas was examined and validated using the training set and validation set.ResultsThe specificity of T2FM for predicting astrocytomas was 100% in both the training and validation sets, while the sensitivity was 42.75% and 67.22%, respectively. Using a classification model of SVM based on radiomics features, among negative T2FM gliomas, the accuracy was above 85% when the prediction score was greater than 0.70 in identifying astrocytomas and above 95% when the prediction score was less than 0.30 in identifying nonastrocytomas.ConclusionsManual screening of positive T2FM gliomas, followed by the SVM classification model to differentiate astrocytomas from negative T2FM gliomas, may be a more effective method for identifying astrocytomas in nonenhancing gliomas.
| S-EPMC10894653 | 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:The current research tested the hypothesis that inversion time (TI) shorter than 2,400 ms under 3T for FLAIR can improve the diagnostic accuracy of the T2-FLAIR mismatch sign for identifying IDHmt, non-CODEL astrocytomas. We prepared three different cohorts; 94 MRI from 76 IDHmt, non-CODEL Lower-grade gliomas (LrGGs), 33 MRI from 31 LrGG under the restriction of FLAIR being acquired with TI < 2,400 ms for 3T or 2,016 ms for 1.5T, and 112 MRI from 112 patients from the TCIA/TCGA dataset for LrGG. The presence or absence of the "T2-FLAIR mismatch sign" was evaluated, and we compared diagnostic accuracies according to TI used for FLAIR acquisition. The T2-FLAIR mismatch sign was more frequently positive when TI was shorter than 2,400 ms under 3T for FLAIR acquisition (p = 0.0009, Fisher's exact test). The T2-FLAIR mismatch sign was positive only for IDHmt, non-CODEL astrocytomas even if we confined the cohort with FLAIR acquired with shorter TI (p = 0.0001, Fisher's exact test). TCIA/TCGA dataset validated that the sensitivity, specificity, PPV, and NPV of the T2-FLAIR mismatch sign to identify IDHmt, non-CODEL astrocytomas improved from 31, 90, 79, and 51% to 67, 94, 92, and 74%, respectively and the area under the curve of ROC improved from 0.63 to 0.87 when FLAIR was acquired with shorter TI. We revealed that TI for FLAIR impacts the T2-FLAIR mismatch sign's diagnostic accuracy and that FLAIR scanned with TI < 2,400 ms in 3T is necessary for LrGG imaging.
| S-EPMC7841010 | biostudies-literature
Project description:Genome-wide DNA methylation profiling of 31 IDH-mutant astrocytoma tumor specimens, of which 14 are from initial surgical resections prior to any radiation or chemotherapy and 17 of which are from a second surgical resection at time of recurrence/progression usually following radiation and/or chemotherapy. For 7 patients (#201-#207), there are paired initial and recurrent tumor samples that were analyzed. For the remaining 17 patients, there are 7 (#208-#214) with only an initial tumor sample analyzed and 10 (#215-#224) with only a recurrent tumor sample analyzed. The Illumina Infinium EPIC 850k Human DNA Methylation Beadchip was used to obtain DNA methylation profiles across approximately 850,000 CpG sites of genomic DNA extracted from formalin-fixed, paraffin-embedded tumor tissue of the 31 IDH-mutant astrocytomas.
2024-11-19 | GSE260850 | GEO
Project description:In the 2016, WHO classification of tumors of the central nervous system, isocitrate dehydrogenase (IDH) mutation is a main classifier for lower grade astrocytomas and IDH-mutated astrocytomas is now regarded as a single group with longer survival. However, the molecular and clinical heterogeneity among IDH mutant lower grade (WHO Grades II/III) astrocytomas have only rarely been investigated. In this study, we recruited 160 IDH mutant lower grade (WHO Grades II/III) astrocytomas, and examined PDGFRA amplification, CDKN2A deletion and CDK4 amplification by FISH analysis, TERT promoter mutation by Sanger sequencing and ATRX loss and p53 expression by immunohistochemistry. We identified PDGFRA amplification, CDKN2A homozygous deletion and CDK4 amplification in 18.8%, 15.0% and 18.1% of our cohort respectively, and these alterations occurred in a mutually exclusive fashion. PDGFRA amplification was associated with shorter PFS (P = 0.0003) and OS (P < 0.0001). In tumors without PDGFRA amplification, CDKN2A homozygous deletion or CDK4 amplification was associated with a shorter OS (P = 0.035). Tumors were divided into three risk groups based on the presence of molecular alterations: high risk (PDGFRA amplification), intermediate risk (CDKN2A deletion or CDK4 amplification) and low risk (neither CDKN2A deletion and CDK4 amplification nor PDGFRA amplification). These three risk groups were significantly different in overall survival with mean survivals of 40.5, 62.9 and 71.5 months. The high-risk group also demonstrated a shorter PFS compared to intermediate- (P = 0.036) and low-risk (P < 0.0001) groups. One limitation of this study is the relatively short follow-up period, a common confounding factor for studies on low-grade tumors. Our data illustrate that IDH mutant lower grade astrocytomas is not a homogeneous group and should be molecularly stratified for risk.
| S-EPMC8018138 | biostudies-literature