de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
Department of Pathology, Cliniques Universitaires Saint-Luc and Université catholique de Louvain, Brussels, Belgium.
Genes Chromosomes Cancer. 2022 Nov;61(11):678-682. doi: 10.1002/gcc.23077. Epub 2022 Jun 21.
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.
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.
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.
PHIP::BRAF is a novel fusion oncogene that can be targeted by trametinib in infantile fibrosarcoma.
ETV6::NTRK3 融合是婴儿型纤维肉瘤（一种影响两岁以下患者的软组织肿瘤）中最常见的基因改变。这些肿瘤较少发生其他激酶基因融合，如 BRAF，其可激活丝裂原活化蛋白激酶通路中的 MEK。这些致癌基因的鉴定和特征对于促进诊断、验证新的治疗方法以及更好地了解这些肿瘤的病理生理学至关重要。
本研究通过 RNA 测序分析了一例 5 天大的婴儿型纤维肉瘤（ETV6::NTRK3 阴性），以鉴定新的融合转录本。通过体外实验对感兴趣的融合进行功能探索，以研究其活性、致癌性和对 MEK 抑制剂曲美替尼的敏感性。
我们鉴定了一种涉及 PHIP 和 BRAF 基因的新型融合。相应的融合蛋白持续激活丝裂原活化蛋白激酶通路，导致成纤维细胞转化。用曲美替尼处理转染细胞可有效抑制 PHIP::BRAF 的信号转导。
PHIP::BRAF 是婴儿型纤维肉瘤中一种新的融合致癌基因，可被曲美替尼靶向治疗。
