A new NFIA:RAF1 fusion activating the MAPK pathway in 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 Raf1 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Christina Westmose
CW
Yde
Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Astrid
A
Sehested
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Àngels
À
Mateu-Regué
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Olga
O
Østrup
Department of Pathology, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
David
D
Scheie
Department of Paediatrics and Adolescent Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Karsten
K
Nysom
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark.
Finn Cilius
FC
Nielsen
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100 Copenhagen, Denmark. Electronic address: caroline.maria.rossing@regionh.dk.
Maria
M
Rossing
D001254:Astrocytoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002675:Child, Preschool; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000378:metabolism*; D048370:MAP Kinase Kinase 2 / Q000378:metabolism*; D008297:Male; D009154:Mutation; D051839:NFI Transcription Factors / Q000235:genetics*; D050596:Oncogene Fusion / Q000235:genetics*; D010766:Phosphorylation; D011379:Prognosis; D000090063:Proto-Oncogene Mas; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*
D014408:Biomarkers, Tumor; C000715470:MAS1 protein, human; D051839:NFI Transcription Factors; C497592:NFIA protein, human; D000090063:Proto-Oncogene Mas; C482128:MAP2K2 protein, human; D019908:Proto-Oncogene Proteins c-raf; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human
MAPK pathway; NFIA:RAF1; fusion gene; pilocytic astrocytoma