Due to their capital diagnostic, prognostic and therapeutic implications, molecular markers have become essential for the management of patients with diffuse gliomas. Among them, IDH mutations have special importance, as they allow to classify diffuse gliomas, they are predictive of prolonged survival and increased sensitivity to alkylating agents and can be targeted by specific inhibitors. IDH-mutant diffuse gliomas deeply differ from IDH-wildtype diffuse gliomas in terms of molecular profile, prognosis and treatment, as different are the pathways of gliomagenesis and progression in the two groups. In the first section of the thesis, we explored the association between 25 glioma risk loci and tumor genotype in a large cohort of glioma patients for whom we disposed of both germline and tumor DNA. Our study confirmed that IDH-mutant and IDH-wildtype gliomas are associated with different susceptibility loci and that certain germline risk loci associate with distinct molecular groups, suggesting a direct involvement in their pathogenesis. In the second section of the thesis, we assessed the performance of two different techniques for the noninvasive detection of IDH mutations. The first technique is based on the identification of IDH1 mutations from the analysis of tumor-derived extracellular vesicles circulating in plasma, a procedure generally referred to as “liquid biopsy”. The second technique is based on the detection of 2-hydroxyglutarate, a metabolite that reflects the presence of IDH mutations, using in vivo magnetic resonance spectroscopy. While the experiments of liquid biopsy posed major challenges due to the limited amount of tumor-derived material circulating in plasma, magnetic resonance spectroscopy proved an overly sensitive and specific technique for the diagnosis and follow-up of patients with IDH-mutant gliomas. In the third section of the thesis, we focused on three rare subsets of IDH-wildtype gliomas with the aim to better characterize their genetic profile, define their prognosis, and assess the prevalence of actionable alterations. We identified different mutational and immunological signatures in high- and low-grade gliomas associated with type 1 neurofibromatosis, we identified recurrent FGFR1 mutations in midline gliomas and frequent FGFR3-TACC3 fusions in low-grade astrocytomas lacking IDH mutations, observations that pave the way to the experimentation of novel therapeutic approaches for these rare tumor types. In the fourth and last section of the thesis, we analyzed the response to targeted treatment in a cohort of adult patients with recurrent or disseminated BRAF-mutant gliomas. The substantial response rate observed in our study encourages the use of RAF/MEK inhibitors in BRAF-mutant gliomas and emphasizes the importance of screening for this rare but actionable alteration.

“MOLECULAR MARKERS IN DIFFUSE GLIOMAS: DIAGNOSTIC AND THERAPEUTIC TARGETS”

BERZERO, GIULIA
2020

Abstract

Due to their capital diagnostic, prognostic and therapeutic implications, molecular markers have become essential for the management of patients with diffuse gliomas. Among them, IDH mutations have special importance, as they allow to classify diffuse gliomas, they are predictive of prolonged survival and increased sensitivity to alkylating agents and can be targeted by specific inhibitors. IDH-mutant diffuse gliomas deeply differ from IDH-wildtype diffuse gliomas in terms of molecular profile, prognosis and treatment, as different are the pathways of gliomagenesis and progression in the two groups. In the first section of the thesis, we explored the association between 25 glioma risk loci and tumor genotype in a large cohort of glioma patients for whom we disposed of both germline and tumor DNA. Our study confirmed that IDH-mutant and IDH-wildtype gliomas are associated with different susceptibility loci and that certain germline risk loci associate with distinct molecular groups, suggesting a direct involvement in their pathogenesis. In the second section of the thesis, we assessed the performance of two different techniques for the noninvasive detection of IDH mutations. The first technique is based on the identification of IDH1 mutations from the analysis of tumor-derived extracellular vesicles circulating in plasma, a procedure generally referred to as “liquid biopsy”. The second technique is based on the detection of 2-hydroxyglutarate, a metabolite that reflects the presence of IDH mutations, using in vivo magnetic resonance spectroscopy. While the experiments of liquid biopsy posed major challenges due to the limited amount of tumor-derived material circulating in plasma, magnetic resonance spectroscopy proved an overly sensitive and specific technique for the diagnosis and follow-up of patients with IDH-mutant gliomas. In the third section of the thesis, we focused on three rare subsets of IDH-wildtype gliomas with the aim to better characterize their genetic profile, define their prognosis, and assess the prevalence of actionable alterations. We identified different mutational and immunological signatures in high- and low-grade gliomas associated with type 1 neurofibromatosis, we identified recurrent FGFR1 mutations in midline gliomas and frequent FGFR3-TACC3 fusions in low-grade astrocytomas lacking IDH mutations, observations that pave the way to the experimentation of novel therapeutic approaches for these rare tumor types. In the fourth and last section of the thesis, we analyzed the response to targeted treatment in a cohort of adult patients with recurrent or disseminated BRAF-mutant gliomas. The substantial response rate observed in our study encourages the use of RAF/MEK inhibitors in BRAF-mutant gliomas and emphasizes the importance of screening for this rare but actionable alteration.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11571/1371676
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