Development Of Diagnosis and Therapy for Low Grade Gliomas
Development of improved treatment for low grade gliomas requires a better understanding of the underlying biology of these tumors. The term low grade glioma encompasses a variety of tumor subtypes each with a different biology that influences clinical outcome. Unique genetic mutations underlie these different subtypes, and these mutations have only recently been identified.
Whole gene sequencing in low grade gliomas revealed that unlike most tumors, few genetic mutations are necessary for oncogenesis in low grade gliomas. The commonest mutations involved abnormalities of the MAPK/ERK pathway although other pathways have been implicated albeit in a minority. The MAPK/ERK pathway mediates critical cellular responses to growth signals and its dysregulation during the rapid growth of a child is fundamental to many of the glial tumors common to that period of life. How mutations in the MAPK/ERK pathway lead to oncogenesis in these tumors is unclear. Such an understanding would be critical if there are to be prevention strategies.
Whole gene sequencing revealed other rarer genetic alterations. Novel observations were duplication of the tyrosine kinase domain of fibroblast growth factor receptor-1 (FGFR1) and rearrangements of MYB or MYBL1. Mutations in the FGFR1 gene involve fusions with TACC genes and involve upregulation of the MPPK/ERK and the P13K pathways. The MYB gene controls a large number of downstream genes and the mechanism by which oncogenesis occurs in low grade gliomas is as yet uncertain. Both FGFR1 and MYB mutations appear confined to diffuse gliomas and appear absent in pilocytic astrocytomas. (Zhang et al, 2013). The prognosis for these rare tumors appears poor and development of novel targeted therapy for them is an urgent necessity
Microarray gene expression analysis of Olivia’s tumor identified a cluster of low grade gliomas with varied biologies but with similarly poor outcomes. Examination of those genes that characterize this cluster of tumors identified FGF1 overexpression as the probable driving genetic event. Identification of the same mutation in a group of biologically differing tumors is significant as this makes them eligible for “basket study” clinical trials - studies that focus on a tumor’s gene mutation regardless of tumor type. This approach has recently shown to be effective in an international clinical trial, published in the New England Journal of Medicine, which show that a drug focused on a single genetic mutation can be effective across multiple cancer types.
We are currently performing whole genome sequencing of Olivia’s group of tumors to confirm the common underlying genetic mutation.
Whole gene sequencing in low grade gliomas revealed that unlike most tumors, few genetic mutations are necessary for oncogenesis in low grade gliomas. The commonest mutations involved abnormalities of the MAPK/ERK pathway although other pathways have been implicated albeit in a minority. The MAPK/ERK pathway mediates critical cellular responses to growth signals and its dysregulation during the rapid growth of a child is fundamental to many of the glial tumors common to that period of life. How mutations in the MAPK/ERK pathway lead to oncogenesis in these tumors is unclear. Such an understanding would be critical if there are to be prevention strategies.
Whole gene sequencing revealed other rarer genetic alterations. Novel observations were duplication of the tyrosine kinase domain of fibroblast growth factor receptor-1 (FGFR1) and rearrangements of MYB or MYBL1. Mutations in the FGFR1 gene involve fusions with TACC genes and involve upregulation of the MPPK/ERK and the P13K pathways. The MYB gene controls a large number of downstream genes and the mechanism by which oncogenesis occurs in low grade gliomas is as yet uncertain. Both FGFR1 and MYB mutations appear confined to diffuse gliomas and appear absent in pilocytic astrocytomas. (Zhang et al, 2013). The prognosis for these rare tumors appears poor and development of novel targeted therapy for them is an urgent necessity
Microarray gene expression analysis of Olivia’s tumor identified a cluster of low grade gliomas with varied biologies but with similarly poor outcomes. Examination of those genes that characterize this cluster of tumors identified FGF1 overexpression as the probable driving genetic event. Identification of the same mutation in a group of biologically differing tumors is significant as this makes them eligible for “basket study” clinical trials - studies that focus on a tumor’s gene mutation regardless of tumor type. This approach has recently shown to be effective in an international clinical trial, published in the New England Journal of Medicine, which show that a drug focused on a single genetic mutation can be effective across multiple cancer types.
We are currently performing whole genome sequencing of Olivia’s group of tumors to confirm the common underlying genetic mutation.