Rare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer.

TitleRare FGFR Oncogenic Alterations in Sequenced Pediatric Solid and Brain Tumors Suggest FGFR Is a Relevant Molecular Target in Childhood Cancer.
Publication TypeJournal Article
Year of Publication2022
AuthorsDe La Vega LLazo, Comeau H, Sallan S, Al-Ibraheemi A, Gupta H, Li YY, Tsai HK, Kang W, Ward A, Church AJ, Kim AR, Pinto NR, Macy ME, Maese LD, Sabnis AJ, Cherniack AD, Lindeman NI, Anderson ME, Cooney TM, Yeo KKiat, Reaman GH, DuBois SG, Collins NB, Johnson BE, Janeway KA, Forrest SJ
JournalJCO Precis Oncol
Date Published2022 Nov
KeywordsBase Sequence, Brain Neoplasms, Carcinogenesis, Child, Glioma, Humans, Microtubule-Associated Proteins, Oncogenes, Protein Kinase Inhibitors

PURPOSE: Multiple FGFR inhibitors are currently in clinical trials enrolling adults with different solid tumors, while very few enroll pediatric patients. We determined the types and frequency of FGFR alterations (FGFR1-4) in pediatric cancers to inform future clinical trial design.

METHODS: Tumors with FGFR alterations were identified from two large cohorts of pediatric solid tumors subjected to targeted DNA sequencing: The Dana-Farber/Boston Children's Profile Study (n = 888) and the multi-institution GAIN/iCAT2 (Genomic Assessment Improves Novel Therapy) Study (n = 571). Data from the combined patient population of 1,395 cases (64 patients were enrolled in both studies) were reviewed and cases in which an FGFR alteration was identified by OncoPanel sequencing were further assessed.

RESULTS: We identified 41 patients with tumors harboring an oncogenic FGFR alteration. Median age at diagnosis was 8 years (range, 6 months-26 years). Diagnoses included 11 rhabdomyosarcomas, nine low-grade gliomas, and 17 other tumor types. Alterations included gain-of-function sequence variants (n = 19), amplifications (n = 10), oncogenic fusions (FGFR3::TACC3 [n = 3], FGFR1::TACC1 [n = 1], FGFR1::EBF2 [n = 1], FGFR1::CLIP2 [n = 1], and FGFR2::CTNNA3 [n = 1]), pathogenic-leaning variants of uncertain significance (n = 4), and amplification in combination with a pathogenic-leaning variant of uncertain significance (n = 1). Two novel FGFR1 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor.

CONCLUSION: In summary, activating FGFR alterations were found in approximately 3% (41/1,395) of pediatric solid tumors, identifying a population of children with cancer who may be eligible and good candidates for trials evaluating FGFR-targeted therapy. Importantly, the genomic and clinical data from this study can help inform drug development in accordance with the Research to Accelerate Cures and Equity for Children Act.

Alternate JournalJCO Precis Oncol
PubMed ID36446043
PubMed Central IDPMC9812632
Grant ListK08 CA218691 / CA / NCI NIH HHS / United States
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