BRAF kinase activation via chromosomal rearrangement in radiation-induced and sporadic thyroid cancer.
Activating point mutations of the BRAF gene have been recently described in a variety of human tumors. In a study published in the Journal of Clinical Investigation, we reported a novel mechanism of activation of this gene via paracentric inversion of chromosome 7q. The fusion protein, AKAP9-BRAF, contains the intact kinase domain and lacks the autoinhibitory N-terminal portion of BRAF. It exhibited constitutive activation of BRAF kinase and was transforming for NIH3T3 cells. This finding represents the first demonstration of RAF activation by chromosomal rearrangement in human tumors. AKAP9-BRAF was more common in radiation-induced thyroid tumors, whereas point mutations of BRAF predominated in sporadic tumors of the same type, demonstrating the association between environmental factors and specific mechanisms of BRAF activation.
Ciampi
Raffaele
R
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0529, USA.
Knauf
Jeffrey A
JA
Rabes
Hartmut M
HM
Fagin
James A
JA
Nikiforov
Yuri E
YE
D000818:Animals; D002453:Cell Cycle; D002869:Chromosome Aberrations; D002874:Chromosome Mapping; D002875:Chromosomes / Q000648:ultrastructure*; D004777:Environment; D004789:Enzyme Activation; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D041681:NIH 3T3 Cells; D009381:Neoplasms, Radiation-Induced / Q000378:metabolism*; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry* / Q000502:physiology; D013964:Thyroid Neoplasms / Q000378:metabolism*
C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf