Second Report of PDE10A-BRAF Fusion in Pediatric Spindle Cell Sarcoma With Infantile Fibrosarcoma-Like Morphology Suggesting PDE10A-BRAF Fusion Is a Recurrent Event

Abstract

Infantile/congenital fibrosarcoma (IFS) is the most common soft tissue tumor in children less than one year of age. The most common anatomic site of IFS is in the extremities or trunk, and rarely in the abdomen or retroperitoneum. Approximately 70-90% of cases are characterized by a distinct t(12;15)(p13;q25) translocation resulting in an ETV6-NTRK3 gene fusion. As such, TRK inhibitors are considered frontline therapy in TRK-fusion positive IFS. The ETV6-NTRK3 fusion is also detected in congenital mesoblastic nephroma (CMN) and less frequently in myeloid leukemias, secretory breast carcinoma, and mammary-type secretory carcinoma of the skin and salivary glands. Infrequently, cases of tumors with IFS-like morphology without the characteristic ETV6-NTRK3 gene fusion have been identified. Herein, an ETV6-NTRK3 fusion negative spindle cell sarcoma with IFS-like morphology subjected to genomic profiling revealed a PDE10A-BRAF fusion, a fusion event that has been detected previously in an isolated case of undifferentiated infantile sarcoma.

Identification of a novel PHIP::BRAF gene fusion in infantile fibrosarcoma

“…In these fusions, the BRAF kinase domain is activated mainly through the loss of its N‐terminal CR1 autoinhibitory domain 20 . In IFS, several fusions involving BRAF have been reported, but not functionally characterized 4,21,22 . In addition, Wegert and colleagues identified intragenic rearrangements of BRAF involving a deletion of the CR1 domain associated with a duplication of exon 2 23 .…”

“…20 In IFS, several fusions involving BRAF have been reported, but not functionally characterized. 4,21,22 In addition, Wegert and colleagues identified intragenic rearrangements of BRAF involving a deletion of the CR1 domain associated with a duplication of exon 2. 23 The CR1 domain contains the RAS-binding domain that negatively regulates BRAF dimerization in the inactive state.…”

Spindle cell sarcoma with KIAA1549‑BRAF resembling infantile fibrosarcoma morphologically: A case report and literature review

“…The characteristics of BRAF-altered spindle cell sarcomas resembling IFS morphologically are not well understood (10,11,(15)(16)(17)(18). To identify the clinical characteristics of BRAF-altered spindle cell sarcomas resembling IFS morphologically, we conducted a literature search of all reports.…”

An unusual fusion gene EML4‐ALK in a patient with congenital mesoblastic nephroma

“…Among mesenchymal tumors, various means of oncogenic signaling through the MAP kinase (e.g., rearrangement of NTRK, RET, BRAF, MET, and RAF1) have been demonstrated in IFS and CMN. [1][2][3][5][6][7][11][12][13][14][15][16][17][18] In addition, in rare cases of CMNs, an oncogenic variant of BRAF (internal BRAF deletion) 5 or activating point mutation of BRAF 13 has been detected.…”

“…The spectrum of so-called "infantile fibrosarcoma and mesoblastic nephroma" has expanded to include tumors with NTRK, MET, RAF1, RET gene fusions, and BRAF fusions and point mutations. BRAF alterations, RET fusions, and NTKR1/2 were previously described in both entities-IFS and CMN, 3,5,[7][8][9][10][11][12][13][14][15] whether RAF1 fusions and MET fusions particularly in IFS. [16][17][18] In this study, we report EML4-ALK gene fusion in a case of a congenital renal tumor resembling CMN in a newborn boy.…”