Identification and targeting of an FGFR fusion in a pediatric thalamic "central oligodendroglioma"

Abstract

Approximately 1-5% of pediatric intracranial tumors originate in the thalamus. While great strides have been made to identify consistent molecular markers in adult oligodendrogliomas, such as the 1p/19q co-deletion, it is widely recognized that pediatric oligodendrogliomas have a vastly different molecular make-up. While pediatric thalamic or "central oligodendrogliomas" are histologically similar to peripheral pediatric oligodendrogliomas, they are behaviorally distinct and likely represent a cohesive, but entirely different entity. We describe a case of a 10-year-old girl who was diagnosed with an anaplastic glioma with features consistent with the aggressive entity often diagnosed as central or thalamic oligodendroglioma. We performed whole-exome (paired tumor and germline DNA) and transcriptome (tumor RNA) sequencing, which demonstrated an FGFR3-PHGDH fusion. We describe this fusion and our rationale for pursuing personalized, targeted therapy for the patient's tumor that may potentially play a role in the treatment of similar cases.

Fig. 1

a Initial scan presenting axial T2 FLAIR image of the central tumor. Heterogenous, 5.1 × 3.8 × 3.4 cm ovoid mass with involvement of the left thalamus and internal capsule. Left lateral ventricle is distorted with displacement of the septum pellucidum and third ventricle. b Three-month follow-up axial T2 FLAIR image of central tumor status post treatment with chemotherapy. Concerning for tumor growth. c H&E-stained paraffin-embedded section showing moderately cellular glial neoplasm composed of relatively monomorphic round cells with clear cytoplasm and distinct cell borders (arrow), as well as arborizing capillaries (arrow heads). d From the same section as c showing calcospherites (arrow heads). e Fusion of FGFR3 with PHGDH. Top panel represents wildtype FGFR3. All exons are represented by blue or red squares while domains are represented by the gray bar (SP=signal peptide, Ig=immunoglobulin-like domain, AB=acid box, TM=transmembrane domain, TK=tyrosine kinase domain). The middle panel represents wildtype PHGDH (SB=substrate-binding domain, NAD(P)=NAD⁺/NADP⁺-binding domain, RD=regulatory domain). The lower panel represents the FGFT3-PHGDH fusion. Fusion occurs intracellularly, at the 3′ end of the FGFR3. FGFR3 exons 1~17 (p.D760) fused in-frame to PHGDH exons 9~12 (p.V316). The extracellular, transmembrane, and kinase domain for FGFR3 are all intact. Standard FGF inhibitors like ponatinib should theoretically work against this fusion assuming they have sufficient ability to cross the BBB. f Copy number profile of FGFR3-PHGDH fusion

Fig. 2

Axial T2 FLAIR image of the thalamic tumor pre-radiation (left), post-radiation (November 2016, center) and after two cycles of ponatinib (March 2017, right). Dimensions of the post-radiation tumor are 45.6 mm × 28.6 mm × 35.0 mm compared to 40.3 mm × 26.6 mm 36.0 mm after two cycles on ponatinib. This represents a 15% reduction in volume