Cerebrovascular diseases and brain cancers are two major types of intracranial disorder that requires surgery. However, patients may experience recurrence even with current treatment, highlighting the importance of understanding the mechanism of the disease for successful treatment development and outcome. In collaboration with neurosurgeons, we focused on two intracranial disorders in this thesis: brain Arteriovenous Malformation (bAVM) and Glioblastoma (GBM).

BAVM, an abnormal blood vessel formation in brain, is the most common cause of intracranial hemorrhage in children, but its etiology remains unclear. To elucidate the molecular pathogenesis of bAVM, we utilized multiple sequencing technologies to characterize the lesions of bAVM, and identify somatic and germline alterations. We...[ Read more ]

Cerebrovascular diseases and brain cancers are two major types of intracranial disorder that requires surgery. However, patients may experience recurrence even with current treatment, highlighting the importance of understanding the mechanism of the disease for successful treatment development and outcome. In collaboration with neurosurgeons, we focused on two intracranial disorders in this thesis: brain Arteriovenous Malformation (bAVM) and Glioblastoma (GBM).

BAVM, an abnormal blood vessel formation in brain, is the most common cause of intracranial hemorrhage in children, but its etiology remains unclear. To elucidate the molecular pathogenesis of bAVM, we utilized multiple sequencing technologies to characterize the lesions of bAVM, and identify somatic and germline alterations. We found somatic KRAS mutations with an incidence of 69.8% (125/179) and significantly associated with intracranial bleeding (p = 0.0072). We also identified 48 non-synonymous de novo germline mutations (DNMs), affecting 46 genes, which were enriched in blood vessel tis-sue and vascular cell types (p < 0.05). Endothelial-to-mesenchymal transition (EndMT) was observed in AVM lesions at the bulk and single-cell levels. Finally, we demonstrate that the DNMs and somatic KRAS mutation convergently promote EndMT in vitro.

GBM is the most common malignant brain cancer characterized by rapid progression and high mortality rates. However, patients benefit differently from using a chemotherapeutic agent, Temozolomide (TMZ), which is part of the current treatment regimen. In this study, we defined TMZ-resistant and sensitive groups from in vitro screening of patient-derived glioma stem-like cells. A machine-learning model was then developed to forecast TMZ response using genomic and transcriptomic signatures in cancer cells of individual patients. In addition, multi-sector TMZ screening revealed intratumoral heterogeneity (ITH) of TMZ resistance.

Collectively, we identified the underlying genetic features potentially associated with disease pathogenesis of AVM, and provided a novel computational tool to predict TMZ resistance in GBM patients.