Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 115, Issue 1, Pages 94-101Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI200523237
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Funding
- NCI NIH HHS [R01 CA50706, R01 CA88041, R01 CA088041, R01 CA050706] Funding Source: Medline
- NCRR NIH HHS [M01 RR08084, M01 RR008084] Funding Source: Medline
- NATIONAL CANCER INSTITUTE [R01CA088041, R01CA050706] Funding Source: NIH RePORTER
- NATIONAL CENTER FOR RESEARCH RESOURCES [M01RR008084] Funding Source: NIH RePORTER
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Genes crucial for cancer development can be mutated via various mechanisms, which may reflect the nature of the mutagen. In thyroid papillary carcinomas, mutations of genes coding for effectors along the MAPK pathway are central for transformation. BRAF point mutation is most common in sporadic tumors. By contrast, radiation-induced tumors are associated with paracentric inversions activating the receptor tyrosine kinases RET and NTRK1. We report here a rearrangement of BRAF via paracentric inversion of chromosome 7q resulting in an in-frame fusion between exons 1-8 of the AKAP9 gene and exons 9-18 of BRAF. The fusion protein contains the protein kinase domain and lacks the autoinhibitory N-terminal portion of BRAF. It has elevated kinase activity and transforms NIH3T3 cells, which provides evidence, for the first time to our knowledge, of in vivo activation of an intracellular effector along the MAPK pathway by recombination. The AKAP9-BRAF fusion was preferentially found in radiation-induced papillary carcinomas developing after a short latency, whereas BRAF point mutations were absent in this group. These data indicate that in thyroid cancer, radiation activates components of the MAPK pathway primarily through chromosomal paracentric inversions, whereas in sporadic forms of the disease, effectors along the same pathway are activated predominantly by point mutations.
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