Oncogenic AKAP9-BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer

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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

Raffaele Ciampi1, Jeffrey A Knauf, Roswitha Kerler

  • 1Department of Pathology and Laboratory Medicine and Division of Endocrinology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0529, USA.

The Journal of Clinical Investigation
|January 5, 2005
PubMed

Insights

Radiation can cause thyroid papillary carcinomas by rearranging the BRAF gene, forming AKAP9-BRAF fusions. This differs from sporadic tumors, which typically have BRAF point mutations, highlighting distinct cancer development pathways.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Mutations in genes regulating the MAPK pathway are central to thyroid papillary carcinoma development.
  • Sporadic tumors often feature BRAF point mutations, while radiation-induced tumors show rearrangements activating receptor tyrosine kinases.

Purpose of the Study:

  • To investigate the mechanism of BRAF gene activation in radiation-induced thyroid papillary carcinomas.
  • To identify novel gene rearrangements in cancer development.

Main Methods:

  • Analysis of chromosomal rearrangements in radiation-induced thyroid papillary carcinomas.
  • Identification of gene fusions using molecular techniques.
  • Functional assessment of the resulting fusion protein in cell transformation assays.

Main Results:

  • A novel in-frame fusion, AKAP9-BRAF, was identified, resulting from a paracentric inversion on chromosome 7q.
  • The AKAP9-BRAF fusion protein exhibits elevated kinase activity and transforms NIH3T3 cells.
  • This fusion was predominantly found in radiation-induced tumors with short latency, and BRAF point mutations were absent in this group.

Conclusions:

  • Chromosomal rearrangements, specifically paracentric inversions leading to gene fusions like AKAP9-BRAF, are a key mechanism for activating MAPK pathway components in radiation-induced thyroid cancer.
  • This contrasts with sporadic thyroid cancers, where BRAF point mutations are the predominant activation mechanism.

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