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

Authors

Lorena Lazo De La Vega, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Hannah Comeau, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Sarah Sallan, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Alyaa Al-Ibraheemi, Boston Children's Hospital, Boston, MA.
Hersh Gupta, Broad Institute of MIT and Harvard, Cambridge, MA.
Yvonne Y. Li, Broad Institute of MIT and Harvard, Cambridge, MA.
Harrison K. Tsai, Boston Children's Hospital, Boston, MA.
Wenjun Kang, University of Chicago, Chicago, IL.
Abigail Ward, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Alanna J. Church, Boston Children's Hospital, Boston, MA.
AeRang Kim, Children's National Hospital, Washington, DC.
Navin R. Pinto, Seattle Children's Hospital, Seattle, WA.
Margaret E. Macy, Children's Hospital of Colorado, Aurora, CO.
Luke D. Maese, Primary Children's Hospital, Salt Lake City, UT.
Amit J. Sabnis, Department of Pediatrics, University of California, San Francisco, San Francisco, CA.
Andrew D. Cherniack, Broad Institute of MIT and Harvard, Cambridge, MA.
Neal I. Lindeman, Harvard Medical School, Boston, MA.
Megan E. Anderson, Harvard Medical School, Boston, MA.
Tabitha M. Cooney, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Kee Kiat Yeo, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Gregory H. Reaman, Oncology Center of Excellence, US Food and Drug Administration, Silver Spring, MD.
Steven G. DuBois, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Natalie B. Collins, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Bruce E. Johnson, Harvard Medical School, Boston, MA.
Katherine A. Janeway, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.
Suzanne J. Forrest, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA.

Document Type

Journal Article

Publication Date

11-1-2022

Journal

JCO precision oncology

Volume

6

DOI

10.1200/PO.22.00390

Abstract

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 alterations () in pediatric cancers to inform future clinical trial design. METHODS: Tumors with 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 alteration was identified by OncoPanel sequencing were further assessed. RESULTS: We identified 41 patients with tumors harboring an oncogenic 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 (:: [n = 3], :: [n = 1], :: [n = 1], :: [n = 1], and :: [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 fusions in two different patients were identified in this cohort, one of whom showed a response to an FGFR inhibitor. CONCLUSION: In summary, activating 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.

Department

Pediatrics

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