Specific germline Nf1 mutations (R681X and R1278P, but not G848R or R1809C) confer a higher risk of optic pathway glioma development in murine models, which we have shown is partially due to their differential effects on the proliferation of the cell of origin for these tumors (neural stem cells in the third ventricular zone; TVZ NSCs). Patients with NF1 are also at risk for developing brainstem gliomas later in childhood as well as high-grade gliomas in adulthood [likely derived from NSCs in the fourth ventricular zone (FVZ) and lateral ventricular zone (LVZ), respectively]. We utilize animal models of NF1 to determine how specific germline mutations affect LVZ and FVZ NSCs at different ages, relevant to glioma risk in these different regions of the brain.
Low-grade gliomas can arise anywhere in the pediatric brain, but tumor location may affect relapse rate and acquisition of neurologic deficits. These tumors are typically driven by mutations activating the MAPK signaling pathway, most frequently the KIAA-1549 BRAF fusion mutation. Notably, incompletely resected tumors in the supratentorial midline region (optic pathway, hypothalamus, thalamus) have a higher rate of serial relapse than incompletely resected tumors elsewhere in the brain, and also a higher incidence of non-BRAF-fusion mutations. We are utilizing a combination of in vitro and in vivo applications to determine how brain location affects NSC response to different oncogenic mutations, the molecular pathways underlying these differences, and whether this correlates with risk of brain tumor formation.
Increased birth weight is associated with an increased risk of optic pathway glioma formation in children with NF1 as well as sporadic glioma in the general population. One of the modifiable factors associated with increased birth weight is higher fat intake during pregnancy. Maternal high-fat diet exposure has also been shown to affect the development of the fetal brain, particularly in the vicinity of the TVZ (location of the cell of origin of NF1-optic pathway glioma). We are using animal models of dietary-induced obesity to determine the effect of maternal weight and/or diet exposure on the NF1-optic pathway glioma cell of origin and tumor penetrance.