Dysregulation of the Hippo signaling pathway and the consequent YAP1 activation is a frequent event in human malignancies, yet the underlying molecular mechanisms are still poorly understood. A pancancer analysis of core Hippo kinases and their candidate regulating molecules revealed few alterations in the canonical Hippo pathway, but very frequent genetic alterations in the FAT family of atypical cadherins. By focusing on head and neck squamous cell carcinoma (HNSCC), which displays frequent FAT1 alterations (29.8%), we provide evidence that FAT1 functional loss results in YAP1 activation. Mechanistically, we found that FAT1 assembles a multimeric Hippo signaling complex (signalome), resulting in activation of core Hippo kinases by TAOKs and consequent YAP1 inactivation. We also show that unrestrained YAP1 acts as an oncogenic driver in HNSCC, and that targeting YAP1 may represent an attractive precision therapeutic option for cancers harboring genomic alterations in the FAT1 tumor suppressor genes.

Background Gliomas are the most common type of primary brain tumor and one of many cancers where males are diagnosed with greater frequency than females. However, little is known about the sex-based molecular differences in glioblastomas (GBMs) or lower grade glioma (non-GBM) subtypes. DNA methylation is an epigenetic mechanism involved in regulating gene transcription. In glioma and other cancers, hypermethylation of specific gene promoters downregulates transcription and may have a profound effect on patient outcome. The purpose of this study was to determine if sex-based methylation differences exist in different glioma subtypes. Methods Molecular and clinical data from glioma patients were obtained from The Cancer Genome Atlas and grouped according to tumor grade and molecular subtype (IDH1/2 mutation and 1p/19q chromosomal deletion). Sex-specific differentially methylated probes (DMPs) were identified in each subtype and further analyzed to determine if they were part of differentially methylated regions (DMRs) or associated with differentially methylated DNA transcription regulatory binding motifs. Results Analysis of methylation data in 4 glioma subtypes revealed unique sets of both sex-specific DMPs and DMRs in each subtype. Motif analysis based on DMP position also identified distinct sex-based sets of DNA-binding motifs that varied according to glioma subtype. Downstream targets of 2 of the GBM-specific transcription binding sites, NFAT5 and KLF6, showed differential gene expression consistent with increased methylation mediating downregulation. Conclusion DNA methylation differences between males and females in 4 glioma molecular subtypes suggest an important, sex-specific role for DNA methylation in epigenetic regulation of gliomagenesis.

Although machine learning (ML) has shown promise across disciplines, out-of-sample generalizability is concerning. This is currently addressed by sharing multi-site data, but such centralization is challenging/infeasible to scale due to various limitations. Federated ML (FL) provides an alternative paradigm for accurate and generalizable ML, by only sharing numerical model updates. Here we present the largest FL study to-date, involving data from 71 sites across 6 continents, to generate an automatic tumor boundary detector for the rare disease of glioblastoma, reporting the largest such dataset in the literature (n = 6, 314). We demonstrate a 33% delineation improvement for the surgically targetable tumor, and 23% for the complete tumor extent, over a publicly trained model. We anticipate our study to: 1) enable more healthcare studies informed by large diverse data, ensuring meaningful results for rare diseases and underrepresented populations, 2) facilitate further analyses for glioblastoma by releasing our consensus model, and 3) demonstrate the FL effectiveness at such scale and task-complexity as a paradigm shift for multi-site collaborations, alleviating the need for data-sharing.

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The use of magnetic resonance imaging (MRI) in healthcare and the emergence of radiology as a practice are both relatively new compared with the classical specialties in medicine. Having its naissance in the 1970s and later adoption in the 1980s, the use of MRI has grown exponentially, consequently engendering exciting new areas of research. One such development is the use of computational techniques to analyze MRI images much like the way a radiologist would. With the advent of affordable, powerful computing hardware and parallel developments in computer vision, MRI image analysis has also witnessed unprecedented growth. Due to the interdisciplinary and complex nature of this subfield, it is important to survey the current landscape and examine the current approaches for analysis and trend trends moving forward.

PURPOSE Multi-parametric MRI and artificial intelligence (AI) methods were previously used to predict peritumoral neoplastic cell infiltration and risk of future recurrence in glioblastoma, in single-institution studies. We hypothesize that important characteristics of peritumoral tissue heterogeneity captured, engineered/selected, and quantified by these methods relate to predictions generalizable in the multi-institutional ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium. METHODS To support further development, generalization, and clinical translation of our proposed method, we trained the AI model on a retrospective cohort of 29 de novo glioblastoma patients from the Hospital of the University of Pennsylvania (UPenn) (Male/Female:20/9, age:22-78 years) followed by evaluation on a prospective multi-institutional cohort of 84 glioblastoma patients (Male/Female:51/33, age:34-89 years) from Case Western Reserve University/University Hospitals (CWRU/UH, 25), New York University (NYU, 13), Ohio State University (OSU, 13), University Hospital Río Hortega (RH, 2), and UPenn (31). Features extracted from pre-resection MRI (T1, T1-Gd, T2, T2-FLAIR, ADC) were used to build our model predicting the spatial pattern of subsequent tumor recurrence. These predictions were evaluated against regions of pathology-confirmed post-resection recurrence. RESULTS Our model predicted the locations that later harbored tumor recurrence with sensitivity 83%, AUC 0.83 (99% CI, 0.73-0.93), and odds ratio 7.23 (99% CI, 7.09-7.37) in the prospective cohort. Odds ratio (99% CI)/AUC(99% CI) per institute were: CWRU/UH, 7.8(7.6-8.1)/0.82(0.75-0.89); NYU, 3.5(3.3-3.6)/0.84(074-0.93); OSU, 7.9(7.6-8.3)/0.8(0.67-0.94); RH, 22.7(20-25.1)/0.94(0.27-1); UPenn, 7.1(6.8-7.3)/0.83(0.76-0.91). CONCLUSION This is the first study that provides relatively extensive multi-institutional validated evidence that AI can provide good predictions of peritumoral neoplastic cell infiltration and future recurrence, by dissecting the MRI signal heterogeneity in peritumoral tissue. Our analyses leveraged the unique dataset of the ReSPOND consortium, which aims to develop and evaluate AI-based biomarkers for individualized prediction and prognostication, by moving from single-institution studies to generalizable, well-validated multi-institutional predictive biomarkers.

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PURPOSE Multi-parametric MRI based radiomic signatures have highlighted the promise of artificial intelligence (AI) in neuro-oncology. However, inter-institution heterogeneity hinders generalization to data from unseen clinical institutions. To this end, we formulated the ReSPOND (Radiomics Signatures for PrecisiON Diagnostics) consortium for glioblastoma. Here, we seek non-invasive generalizable radiomic signatures from routine clinically-acquired MRI for prognostic stratification of glioblastoma patients. METHODS We identified a retrospective cohort of 606 patients with near/gross total tumor resection ( >90%), from 13 geographically-diverse institutions. All pre-operative structural MRI scans (T1,T1-Gd,T2,T2-FLAIR) were aligned to a common anatomical atlas. An automatic algorithm segmented the whole tumors (WTs) into 3 sub-compartments, i.e., enhancing (ET), necrotic core (NC), and peritumoral T2-FLAIR signal abnormality (ED). The combination of ET+NC defines the tumor core (TC). Quantitative radiomic features were extracted to generate our AI model to stratify patients into short- (< 14mts) and long-survivors ( >14mts). The model trained on 276 patients from a single institution was independently validated on 330 unseen patients from 12 left-out institutions, using the area-under-the-receiver-operating-characteristic-curve (AUC). RESULTS Each feature individually offered certain (limited but reproducible) value for identifying short-survivors: 1) TC closer to lateral ventricles (AUC=0.62); 2) larger ET/brain (AUC=0.61); 3) larger TC/brain (AUC=0.59); 4) larger WT/brain (AUC=0.55); 5) larger ET/WT (AUC=0.59); 6) smaller ED/WT (AUC=0.57); 7) larger ventricle deformations (AUC=0.6). Integrating all features and age, through a multivariate AI model, resulted in higher accuracy (AUC=0.7; 95% C.I.,0.64-0.77). CONCLUSION Prognostic stratification using basic radiomic features is highly reproducible across diverse institutions and patient populations. Multivariate integration yields relatively more accurate and generalizable radiomic signatures, across institutions. Our results offer promise for generalizable non-invasive in vivo signatures of survival prediction in patients with glioblastoma. Extracted features from clinically-acquired imaging, renders these signatures easier for clinical translation. Large-scale evaluation could contribute to improving patient management and treatment planning. *Indicates equal authorship.