Prognostic value of DNA methylation subclassification, aneuploidy, and CDKN2A/B homozygous deletion in predicting clinical outcome of IDH mutant astrocytomas.

BACKGROUND: Isocitrate dehydrogenase (IDH) mutant astrocytoma grading, until recently, has been entirely based on morphology. The 5th edition of the Central Nervous System World Health Organization (WHO) introduces CDKN2A/B homozygous deletion as a biomarker of grade 4. We sought to investigate the prognostic impact of DNA methylation-derived molecular biomarkers for IDH mutant astrocytoma. METHODS: We analyzed 98 IDH mutant astrocytomas diagnosed at NYU Langone Health between 2014 and 2022. We reviewed DNA methylation subclass, CDKN2A/B homozygous deletion, and ploidy and correlated molecular biomarkers with histological grade, progression free (PFS), and overall (OS) survival. Findings were confirmed using 2 independent validation cohorts. RESULTS: There was no significant difference in OS or PFS when stratified by histologic WHO grade alone, copy number complexity, or extent of resection. OS was significantly different when patients were stratified either by CDKN2A/B homozygous deletion or by DNA methylation subclass (P value = .0286 and .0016, respectively). None of the molecular biomarkers were associated with significantly better PFS, although DNA methylation classification showed a trend (P value = .0534). CONCLUSIONS: The current WHO recognized grading criteria for IDH mutant astrocytomas show limited prognostic value. Stratification based on DNA methylation shows superior prognostic value for OS.

Predicting methylation class from diffusely infiltrating adult gliomas using multimodality MRI data.

Background: Radiogenomic studies of adult-type diffuse gliomas have used magnetic resonance imaging (MRI) data to infer tumor attributes, including abnormalities such as IDH-mutation status and 1p19q deletion. This approach is effective but does not generalize to tumor types that lack highly recurrent alterations. Tumors have intrinsic DNA methylation patterns and can be grouped into stable methylation classes even when lacking recurrent mutations or copy number changes. The purpose of this study was to prove the principle that a tumor's DNA-methylation class could be used as a predictive feature for radiogenomic modeling. Methods: Using a custom DNA methylation-based classification model, molecular classes were assigned to diffuse gliomas in The Cancer Genome Atlas (TCGA) dataset. We then constructed and validated machine learning models to predict a tumor's methylation family or subclass from matched multisequence MRI data using either extracted radiomic features or directly from MRI images. Results: For models using extracted radiomic features, we demonstrated top accuracies above 90% for predicting IDH-glioma and GBM-IDHwt methylation families, IDH-mutant tumor methylation subclasses, or GBM-IDHwt molecular subclasses. Classification models utilizing MRI images directly demonstrated average accuracies of 80.6% for predicting methylation families, compared to 87.2% and 89.0% for differentiating IDH-mutated astrocytomas from oligodendrogliomas and glioblastoma molecular subclasses, respectively. Conclusions: These findings demonstrate that MRI-based machine learning models can effectively predict the methylation class of brain tumors. Given appropriate datasets, this approach could generalize to most brain tumor types, expanding the number and types of tumors that could be used to develop radiomic or radiogenomic models.

Microscopic nuclei classification, segmentation, and detection with improved deep convolutional neural networks (DCNN).

BACKGROUND: Nuclei classification, segmentation, and detection from pathological images are challenging tasks due to cellular heterogeneity in the Whole Slide Images (WSI). METHODS: In this work, we propose advanced DCNN models for nuclei classification, segmentation, and detection tasks. The Densely Connected Neural Network (DCNN) and Densely Connected Recurrent Convolutional Network (DCRN) models are applied for the nuclei classification tasks. The Recurrent Residual U-Net (R2U-Net) and the R2UNet-based regression model named the University of Dayton Net (UD-Net) are applied for nuclei segmentation and detection tasks respectively. The experiments are conducted on publicly available datasets, including Routine Colon Cancer (RCC) classification and detection and the Nuclei Segmentation Challenge 2018 datasets for segmentation tasks. The experimental results were evaluated with a five-fold cross-validation method, and the average testing results are compared against the existing approaches in terms of precision, recall, Dice Coefficient (DC), Mean Squared Error (MSE), F1-score, and overall testing accuracy by calculating pixels and cell-level analysis. RESULTS: The results demonstrate around 2.6% and 1.7% higher performance in terms of F1-score for nuclei classification and detection tasks when compared to the recently published DCNN based method. Also, for nuclei segmentation, the R2U-Net shows around 91.90% average testing accuracy in terms of DC, which is around 1.54% higher than the U-Net model. CONCLUSION: The proposed methods demonstrate robustness with better quantitative and qualitative results in three different tasks for analyzing the WSI.