A new NFIA:RAF1 fusion activating the MAPK pathway in pilocytic astrocytoma

作者：Yde Christina Westmose; Sehested Astrid; Mateu Regue Angels; Ostrup Olga; Scheie David; Nysom Karsten; Nielsen Finn Cilius; Rossing Maria

来源：Cancer Genetics, 2016, 209(10): 440-444.

DOI：10.1016/j.cancergen.2016.09.002

• NFIA:RAF1
• fusion gene
• MAPK pathway
• pilocytic astrocytoma

Pilocytic astrocytoma (PA) is one of the most common brain cancers among children and activation of the Mitogen-Activated Protein Kinase (MAPK) pathway is considered the hallmark. In the majority of cases, oncogenic BRAF fusions or BRAF V600E mutations are observed, while RAF1 or NF1 alterations are more rarely found. However, in some cases, no apparent cancer driver events can be identified. Here, we describe a novel fusion between the transcription factor nuclear factor 1A (NFIA) and Raf-1 proto-oncogene (RAF1) in a 5-year old boy with PA. The novel fusion was identified as part of a comprehensive genomic tumor profiling. We show that the NFIA:RAF1 fusion results in constitutive Raft kinase activity, leading to activation of downstream MEK1/2 cascade and increased proliferation of cancer cells. The NFIA:RAF1 fusion displayed distinct subcellular localization towards the plasma membrane indicative of Raf-1 activation, in contrast to both wild type NFIA and Raf-1, which were localized in the nucleus and cytoplasm, respectively. In conclusion, our data support the existence of rare oncogenic RAF1 fusions with constitutive Raf-1 activity. This highlights the need for broad genetic testing in order to refine diagnostics of PA and to unravel potential treatment options, e.g. with MEK inhibitors.

• 出版日期2016-10