Multi-faceted computational assessment of risk and progression in oligodendroglioma implicates NOTCH and PI3K pathways

Abstract

Oligodendrogliomas are diffusely infiltrative gliomas defined by IDH-mutation and co-deletion of 1p/19q. They have highly variable clinical courses, with survivals ranging from 6 months to over 20 years, but little is known regarding the pathways involved with their progression or optimal markers for stratifying risk. We utilized machine-learning approaches with genomic data from The Cancer Genome Atlas to objectively identify molecular factors associated with clinical outcomes of oligodendroglioma and extended these findings to study signaling pathways implicated in oncogenesis and clinical endpoints associated with glioma progression. Our multi-faceted computational approach uncovered key genetic alterations associated with disease progression and shorter survival in oligodendroglioma and specifically identified Notch pathway inactivation and PI3K pathway activation as the most strongly associated with MRI and pathology findings of advanced disease and poor clinical outcome. Our findings that Notch pathway inactivation and PI3K pathway activation are associated with advanced disease and survival risk will pave the way for clinically relevant markers of disease progression and therapeutic targets to improve clinical outcomes. Furthermore, our approach demonstrates the strength of machine learning and computational methods for identifying genetic events critical to disease progression in the era of big data and precision medicine.

Oncogenic and Tumor-Suppressive Functions of NOTCH Signaling in Glioma

“…These mutations are particularly frequent in the genes encoding the NOTCH1 and NOTCH2 receptors but less common in NOTCH3/4, and occur at similar positions to those demonstrated experimentally to inactivate NOTCH1 function in epithelial cancers [ 24 , 25 , 26 , 133 ]. In addition, less frequent mutations in the RBPJ gene were detected in LGG samples and were mutually exclusive with NOTCH1 mutations [ 134 ]. Accordingly, the expression of some NOTCH target genes is downregulated in NOTCH/RBPJ mutant gliomas, indicating pathway inactivation [ 24 , 26 , 134 ].…”

“…In addition, less frequent mutations in the RBPJ gene were detected in LGG samples and were mutually exclusive with NOTCH1 mutations [ 134 ]. Accordingly, the expression of some NOTCH target genes is downregulated in NOTCH/RBPJ mutant gliomas, indicating pathway inactivation [ 24 , 26 , 134 ]. Expression of the proliferation marker MKI67 was found to be augmented in NOTCH1/RBPJ mutant brain tumors with low HES/HEY expression levels [ 134 ], and NOTCH mutations were a high-risk factor associated with shorter patient survival [ 135 ], suggesting that NOTCH signaling inhibition contributes to increased glioma aggressiveness.…”

“…Accordingly, the expression of some NOTCH target genes is downregulated in NOTCH/RBPJ mutant gliomas, indicating pathway inactivation [ 24 , 26 , 134 ]. Expression of the proliferation marker MKI67 was found to be augmented in NOTCH1/RBPJ mutant brain tumors with low HES/HEY expression levels [ 134 ], and NOTCH mutations were a high-risk factor associated with shorter patient survival [ 135 ], suggesting that NOTCH signaling inhibition contributes to increased glioma aggressiveness. Consistent with this, frequent NOTCH pathway alterations were also detected when comparing progressed tumors with their corresponding lower-grade counterparts [ 26 ].…”

Characterization of longitudinal transformation of T2-hyperintensity in oligodendroglioma

“…The proper oncological treatment of oligodendroglioma represents a challenge due to the highly variable clinical course of the disease with survival rates between few years and more than two decades [4]. Two crucial prospective trials over the past few years showed a favorable response to combined radio-and chemotherapy in WHO grade III oligodendroglioma and oligoastrocytoma [10,11].…”

“…Although oligodendrogliomas show highly variable clinical courses with overall survival rates ranging between 6 months and more than 20 years [4], the prognosis is relatively favorable with an average long-term survival of about 15 years. The treatment of oligodendroglioma includes surgical resection, radiotherapy and chemotherapy.…”