Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma. Issue 2 (14th January 2021)

• Record Type: Journal Article
• Authors: Fomchenko, Elena I.; Reeves, Benjamin C.; Sullivan, William; Marks, Asher M.; Huttner, Anita; Kahle, Kristopher T.; Erson‐Omay, E. Zeynep
• Is Part Of: Molecular genetics & genomic medicine. Volume 9:Issue 2(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-01-14
• Subjects: FGFR inhibitor resistance -- FGFR1 mutation -- FGFR1 p.K656E -- FGFR1 p.V561M -- pilomyxoid astrocytoma -- whole exome sequencing; Medical genetics -- Periodicals; Genomics -- Periodicals; 616.042
• DOI: 10.1002/mgg3.1597
• Languages: English
• ISSNs: 2324-9269

Abstract

Abstract: Background: Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma, not graded by WHO, frequently located in hypothalamic/chiasmatic region, affecting diencephalic structures, and characterized by shorter survival and high recurrence rates. Pilomyxoid astrocytoma management remains controversial, with pathologic tissue diagnosis and relief of mass effect being the main goals of surgery while avoiding treatment‐related morbidity, including vision loss, panhypopituitarism, and hypothalamic dysfunction. Chemotherapy (typically vincristine and carboplatin) in all pediatric patients and radiation therapy in pediatric patients over 5 years of age are used for treatment. Methods: We report clinical presentation, surgical management, and whole exome sequencing results in a pediatric patient with the subtotally resected pilomyxoid astrocytoma. Results: We identified two somatic activating missense mutations affecting FGFR1, including FGFR1 p.K656E and FGFR1 p.V561M. While the former is a known hotspot mutation that is both activating and transforming, the latter has been described as a gatekeeper mutation imparting resistance to FGFR inhibitors. Interestingly, both mutations were present with similar variant allele frequency within the tumor. Conclusion: Similar variant allele frequencies of FGFR1 p.K656E and FGFR1 p.V561M mutations in our patient's tumor suggest that these mutations may have occurred at similar time points. Use of FGFR inhibitors in addition to STAT3 or PI3K/mTOR inhibition may prove a useful strategy in targeting our patient's pilomyxoid astrocytoma. Abstract : Pilomyxoid astrocytomas are an aggressive subtype of astrocytoma, not graded by WHO, frequently located in hypothalamic/chiasmatic regions, affecting diencephalic structures, and characterized by shorter survival and high recurrence rates; their management remains controversial. We describe a pediatric patient with a pilomyxoid astrocytoma. We identified a known hotspot mutation FGFR1 p.K656E that is both activating and transforming, and a gatekeeper mutation FGFR1 p.V561M imparting resistance to FGFR inhibitors. Use of FGFR inhibitors in addition to STAT3 or PI3K/mTOR inhibition may prove a useful strategy in targeting our patient's pilomyxoid astrocytoma.