Low-grade gliomas are a type of brain tumor that affects mainly children and young adults and is associated with drug-resistant epilepsy. The treatment of choice is surgery, but it is not always viable due to technical difficulties. Also, tumor relapse is not rare and can lead to seizure outbreaks, highlighting a strong need for novel therapeutic approaches to improve the quality of life of these young patients. In a previous study, led by Dr Barbara Rivera identified recurrent highly oncogenic mutations in a significant proportion of low-grade glioma, setting a valuable step towards tumor prevention and treatment. These mutations promoted the abnormal expression of FGFR1, a protein involved in cell division and differentiation that can promote tumoral growth. Moreover, they noticed the appearance of secondary mutations and their inheritability, which increased the risk of developing these tumors. Indeed, these FGFR1 alterations are responsible for a considerable proportion of all glioma cases, but the precise mechanisms behind this have not been properly described. Thus, identifying the molecular tumorigenic mechanisms linked to FGFR1 mutations and their combinations in a single tumor could help find novel therapeutic approaches for patients with glioma and other types of FGFR1 mutated brain tumors.
Now, the Rare TumorS lab within the IDIBELL and ICO hereditary cancer group has shed some more light on these puzzling oncogenic mutations. The team, led by Dr Barbara Rivera, started by analyzing genetic data from GENIE, the largest tumor cohort publicly available so far. They confirmed that, although FGFR1 is a driver of many tumor types, the recurrence of secondary mutations is a feature of gliomas. This underscores the importance of their study in an adequate cellular context. Next, they used advanced molecular and cellular approaches like BioID-based proximity labeling and CRISPR-engineered brain tumor cell lines to prove which molecular mechanisms and phenotypes are activated by the given mutations. Overall, they found out that while the most recurrent FGFR1 mutations lead to the accumulation of an oncogenic protein, the combination of mutations in FGFR1 fine-tunes its activity to a level that promotes tumor formation that is tolerated during brain development and allows low grade tumor growth. Still, future efforts are necessary to confirm this modulatory ability for other genetic variant combinations.
Although far from clinical application, IDIBELL researcher and study first author Dr Jacopo Boni feels optimistic about the results: “Altogether, the findings reveal a previously unrecognized mechanism in which co-occurring mutations in the FGFR1 gene cooperate to shape tumor behavior. These insights may inform future design of mutation-specific therapeutic approaches, including drugs that target FGFR1 stability or degradation pathways, to improve treatment options for children with FGFR1-driven brain tumors.”
Video abstract of the study:
The Bellvitge Biomedical Research Institute (IDIBELL) is a research center established in 2004 specialized in cancer, neuroscience, translational medicine, and regenerative medicine. It counts on a team of more than 1.500 professionals who, from 73 research groups, publish more than 1.400 scientific articles per year. IDIBELL is participated by the Bellvitge University Hospital and the Viladecans Hospital of the Catalan Institute of Health, the Catalan Institute of Oncology, the University of Barcelona, and the City Council of L’Hospitalet de Llobregat.
IDIBELL is a member of the Campus of International Excellence of the University of Barcelona HUBc and is part of the CERCA institution of the Generalitat de Catalunya. In 2009 it became one of the first five Spanish research centers accredited as a health research institute by the Carlos III Health Institute. In addition, it is part of the “HR Excellence in Research” program of the European Union and is a member of EATRIS and REGIC. Since 2018, IDIBELL has been an Accredited Center of the AECC Scientific Foundation (FCAECC).