DNA copy number analysis of Grade II-III and Grade IV gliomas reveals differences in molecular ontogeny including chromothripsis associated with IDH mutation status

Introduction: 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 (IDHmut) and wild-type (IDHwt) 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 IDHmut and IDHwt infiltrating gliomas using molecular inversion probe arrays. Results: Ninety four patient samples were divided into four groups: Grade II-III IDHwt (n = 17), Grade II-III IDHmut (n = 28), GBM IDHwt (n = 25), and GBM IDHmut (n = 24). We validated prior observations that IDHwt GBM have a high frequency of chromosome 7 gain (including EGFR) and chromosome 10 loss (including PTEN) compared with IDHmut GBM. Hierarchical clustering of IDHmut gliomas demonstrated distinct CNA patterns distinguishing lower grade gliomas versus GBM. However, similar hierarchical clustering of IDHwt gliomas demonstrated no CNA distinction between lower grade glioma and GBM. Functional analyses showed that IDHwt gliomas had more chromosome gains in regions containing receptor tyrosine kinase pathways. In contrast, IDHmut 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 IDHmut gliomas was the loss of chromosomal regions surrounding PTEN. IDHmut GBM tumors demonstrated significantly higher levels of overall CNAs compared to lower grade IDHmut tumors and all grades of IDHwt tumors, and IDHmut GBMs also demonstrated significant increase in incidence of chromothripsis. Conclusions: Taken together, these analyses demonstrate distinct molecular ontogeny between IDHwt and IDHmut gliomas. Our data also support the novel findings that malignant progression of IDHmut gliomas to GBM involves increased genomic instability and genomic catastrophe, while IDHwt lower grade tumors are virtually identical to GBMs at the level of DNA copy number alterations.