Isocitrate dehydrogenase (IDH) mutation status and grade define subgroups of diffuse gliomas differing based on age, tumor location, presentation, and prognosis. While some biologic differences between IDH mutated (IDH mut) and wild-type (IDH wt) gliomas are clear, the distinct alterations associated with progression of the two subtypes to glioblastoma (GBM, Grade IV) have not been well described. We analyzed copy number alterations (CNAs) across grades (Grade II–III and GBM) in both IDH mut and IDH wt infiltrating gliomas using molecular inversion probe arrays. Ninety four patient samples were divided into four groups: Grade II–III IDH wt (n = 17), Grade II–III IDH mut (n = 28), GBM IDH wt (n = 25), and GBM IDH mut (n = 24). We validated prior observations that IDH wt GBM have a high frequency of chromosome 7 gain (including EGFR) and chromosome 10 loss (including PTEN) compared with IDH mut GBM. Hierarchical clustering of IDH mut gliomas demonstrated distinct CNA patterns distinguishing lower grade gliomas versus GBM. However, similar hierarchical clustering of IDH wt gliomas demonstrated no CNA distinction between lower grade glioma and GBM. Functional analyses showed that IDH wt gliomas had more chromosome gains in regions containing receptor tyrosine kinase pathways. In contrast, IDH mut gliomas more commonly demonstrated amplification of cyclins and cyclin dependent kinase genes. One of the most common alterations associated with transformation of lower grade to GBM IDH mut gliomas was the loss of chromosomal regions surrounding PTEN. IDH mut GBM tumors demonstrated significantly higher levels of overall CNAs compared to lower grade IDH mut tumors and all grades of IDH wt tumors, and IDH mut GBMs also demonstrated significant increase in incidence of chromothripsis. Taken together, these analyses demonstrate distinct molecular ontogeny between IDH wt and IDH mut gliomas. Our data also support the novel findings that malignant progression of IDH mut gliomas to GBM involves increased genomic instability and genomic catastrophe, while IDH wt lower grade tumors are virtually identical to GBMs at the level of DNA copy number alterations.

The vertebrate heart is one of the first organs to form, and its early function and morphogenesis are crucial for continued embryonic development. Here we analyze the effects of loss of Heart adaptor protein 1 (Hadp1), which we show is required for normal function and morphogenesis of the embryonic zebrafish heart. Hadp1 is a pleckstrin homology (PH)-domain-containing protein whose expression is enriched in embryonic cardiomyocytes. Knockdown of hadp1 in zebrafish embryos reduced cardiac contractility and altered late myocyte differentiation. By using optical mapping and submaximal levels of hadp1 knockdown, we observed profound effects on Ca²⁺ handling and on action potential duration in the absence of morphological defects, suggesting that Hadp1 plays a major role in the regulation of intracellular Ca²⁺ handling in the heart. Hadp1 interacts with phosphatidylinositol 4-phosphate [PI4P; also known as PtdIns(4)P] derivatives via its PH domain, and its subcellular localization is dependent upon this motif. Pharmacological blockade of the synthesis of PI4P derivatives in vivo phenocopied the loss of hadp1 in zebrafish. Collectively, these results demonstrate that hadp1 is required for normal cardiac function and morphogenesis during embryogenesis, and suggest that hadp1 modulates Ca²⁺ handling in the heart through its interaction with phosphatidylinositols.