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

Abstract

Introduction:The ETV6::NTRK3 fusion is the most common gene alteration in infantile fibrosarcoma, a soft tissue tumor affecting patients under two years of age.Less frequently, these tumors harbor fusions of genes encoding other kinases, such as BRAF, which activates MEK in the mitogen-activated protein kinase pathway.The identification and characterization of these oncogenes are crucial to facilitate diagnosis, validate new treatments, and better understand the pathophysiology of these neoplasms.Methods: Herein, we analyzed an ETV6::NTRK3-negative infantile fibrosarcoma from a 5-day-old patient by RNA-sequencing to identify new fusion transcripts. Functional exploration of the fusion of interest was performed by in vitro assays to study its activity, oncogenicity, and sensitivity to the MEK inhibitor trametinib.Results: We identified a novel fusion involving the PHIP and BRAF genes. The corresponding fusion protein constitutively activated the mitogen-activated protein kinase pathway, resulting in fibroblast transformation. Treatment of transfected cells with trametinib effectively inhibited signaling by PHIP::BRAF.

Progressive insights into fibrosarcoma diagnosis and treatment: leveraging fusion genes for advancements

“…This case exhibited near-complete responsiveness to crizotinib treatment ( Wong et al, 2016 ). Furthermore, Boulouadnine et al recently reported a CFS case with a novel PHIP-BRAF fusion gene, proposing it as a potential target for trametinib therapy ( Boulouadnine et al, 2022 ). These instances of CFS with rare fusion genes not only expand our understanding but also introduce new therapeutic avenues for managing CFS patients.…”