Lg-26germline and Somatic Fgfr1 Abnormalities in Dysembryoplastic Neuroepithelial Tumors

Rivera, Bárbara; Gayden, Tenzin; Carrot-Zhang, Jian; Nadaf, Javad; Boshari, Talia; Faury, Damien; Zeinieh, Michele; Blanc, R; Burk, David L.; Fahiminiya, Somayyeh; Bareke, Eric; Schüller, Ulrich; Monoranu, Camelia; Sträter, Ronald; Kerl, Kornelius; Niederstadt, Thomas; Kurlemann, Gerhard; Ellezam, Benjamin; Michalak, Zuzanna; Thom, Maria; Lockhart, Paul J.; Leventer, Richard J.; Ohm, Milou; MacGregor, Duncan; Jones, David; Karamchandani, Jason; Greenwood, Celia; Berghuis, Albert M.; Bens, Susanne; Siebert, Reiner; Zakrzewska, Magdalena; Liberski, Paweł P.; Zakrzewski, Krzysztof; Sisodiya, Sanjay M.; Paulus, Werner; Albrecht, Steffen; Hasselblatt, Martin; Jabado, Nada; Foulkes, William D.; Majewski, Jacek

doi:10.1093/neuonc/now075.26

Cited by 3 publications

(7 citation statements)

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“…Although the mechanism remains unclear, it does not appear to be related to Ki67 proliferation index or microvascular proliferation, but is potentially mediated by FGFR1 effects other than the MAPK pathway (Karthigeyan et al, 2019;Linscott et al, 2008). The mutation we identified, FGFR1 p.K656E affecting tyrosine kinase domain of FGFR1 is a gain-of-function hotspot mutation that is both activating (i.e., resulting in constitutively active receptor signaling) and transforming (Hart et al, 2000), and has been previously reported in neuroepithelial tumors, rosette forming glioneuronal tumors and multiple other cancers within COSMIC database (Forbes et al, 2017;Gessi et al, 2014;Helsten et al, 2016;Jones et al, 2013;Rivera et al, 2016). Another mutation we identified, FGFR1 p.V561M, has not been described in primary brain tumors.…”

Section: Discussionmentioning

confidence: 60%

“…Such pressure, however, could represent the preponderance of various mutations to activate different downstream pathways depending on the mutation type, for example, by varying affinity for secondary adapter proteins to activate PI3K versus MAPK pathways, or the ability to preferentially directly activate STAT versus PLCγ pathways depending on the type of mutation, resulting in dose-related effects. Rivera et al propose a mechanism whereby presence of multiple mutations results in balanced signaling, requiring multiple enabling mutations and resulting in benign tumor behavior (Rivera et al, 2016). A similar mechanism of enhanced oncogenicity resulting from combinations of functionally weak, infrequent mutations has been supported by recent pan-cancer analysis (Saito et al, 2020).…”

Section: Discussionmentioning

confidence: 97%

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Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma

Fomchenko

Reeves

Sullivan

et al. 2021

Molec Gen & Gen Med

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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.

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Section: Discussionmentioning

confidence: 60%

Section: Discussionmentioning

confidence: 97%

Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma

Fomchenko

Reeves

Sullivan

et al. 2021

Molec Gen & Gen Med

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“…A variety of genomic alterations have been reported in DNTs, although diagnostically specific changes are not established. Nevertheless, fibroblast growth factor 1 receptor (FGFR1) has been frequently activated in DNTs (10,20). Among FGFR1 alterations, internal tandem duplication (ITD) of the tyrosine kinase domain (TKD) is the most common mutation, which was reported in 40~60% of DNTs.…”

Section: Discussionmentioning

confidence: 99%

“…Other genomic alterations include BRAF p.V600E and copy number chromosome gains (21). Thefrequency of BRAF alterations in DNTs remains inconclusive among different studies (22,23), with several studies failing to identify BRAF alterations in their DNTs cohorts (20,24).…”

Section: Discussionmentioning

confidence: 99%

Case Report: A novel LHFPL3::NTRK2 fusion in dysembryoplastic neuroepithelial tumor

et al. 2022

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Neurotrophic tyrosine receptor kinase (NTRK) rearrangements are oncogenic drivers of various types of adult and pediatric tumors, including gliomas. However, NTRK rearrangements are extremely rare in glioneuronal tumors. Here, we report a novel NTRK2 rearrangement in a 24-year-old female with dysembryoplastic neuroepithelial tumor (DNT), a circumscribed WHO grade I benign tumor associated with epilepsy. By utilizing targeted RNA next-generation sequencing (NGS), fluorescence in situ hybridization (FISH), reverse transcriptase PCR (RT-PCR), and Sanger sequencing, we verified an in-frame fusion between NTRK2 and the lipoma HMGIC fusion partner-like 3 (LHFPL3). This oncogenic gene rearrangement involves 5’ LHFPL3 and 3’ NTRK2, retaining the entire tyrosine kinase domain of NTRK2 genes. Moreover, the targeted DNA NGS analysis revealed an IDH1 (p.R132H) mutation, a surprising finding in this type of tumor. The pathogenic mechanism of the LHFPL3::NTRK2 in this case likely involves aberrant dimerization and constitutive activation of RTK signaling pathways.

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“…Glioneuronal tumors occasionally harbor potentially targetable molecular alterations (Table 1). In DNETs, germline or somatic FGFR1 mutations are common, while BRAF p.V600E mutations are rare (31). In gangliogliomas, BRAF p.V600E mutations occur in 10-60% of cases (depending on the tumor location).…”

Section: Clinical Approach To Glioneuronal Tumors In Aya and Relevanc...mentioning

confidence: 99%

Molecular testing for adolescent and young adult central nervous system tumors: A Canadian guideline

et al. 2022

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The 2021 World Health Organization (WHO) classification of CNS tumors incorporates molecular signatures with histology and has highlighted differences across pediatric vs adult-type CNS tumors. However, adolescent and young adults (AYA; aged 15–39), can suffer from tumors across this spectrum and is a recognized orphan population that requires multidisciplinary, specialized care, and often through a transition phase. To advocate for a uniform testing strategy in AYAs, pediatric and adult specialists from neuro-oncology, radiation oncology, neuropathology, and neurosurgery helped develop this review and testing framework through the Canadian AYA Neuro-Oncology Consortium. We propose a comprehensive approach to molecular testing in this unique population, based on the recent tumor classification and within the clinical framework of the provincial health care systems in Canada.Contributions to the fieldWhile there are guidelines for testing in adult and pediatric CNS tumor populations, there is no consensus testing for AYA patients whose care occur in both pediatric and adult hospitals. Our review of the literature and guideline adopts a resource-effective and clinically-oriented approach to improve diagnosis and prognostication of brain tumors in the AYA population, as part of a nation-wide initiative to improve care for AYA patients.

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Lg-26germline and Somatic Fgfr1 Abnormalities in Dysembryoplastic Neuroepithelial Tumors

Cited by 3 publications

References 0 publications

Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma

Dual activating FGFR1 mutations in pediatric pilomyxoid astrocytoma

Case Report: A novel LHFPL3::NTRK2 fusion in dysembryoplastic neuroepithelial tumor

Molecular testing for adolescent and young adult central nervous system tumors: A Canadian guideline

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