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

Abstract

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.

The role of nuclear organization in cancer

“…As transcriptionally active loci appear to be located at the boundaries, these correlations also support suggestions that active loci have a greater Gene fusions can also arise from intrachromosomal rearrangements such as inversions or DNA copy number gains. For example, the BRAF oncogene fuses with the AKAP9 and KIAA1549 genes as a result of inversions and copy number gains within chromosome 7 in papillary thyroid carcinoma and pilocytic astrocytoma, respectively [50,51]. Papillary thyroid carcinoma has similar gene fusions, such as NTRK1-TPR or RET-H4 and RET-NCO4 arising from rearrangements within chromosomes 1 and 10, respectively.…”

Raf kinases: Oncogenesis and drug discovery

“…52 In radiation-induced thyroid papillary carcinomas another type of B-RAF mutation leading to a novel mode of B-RAF activation was found. 94 The paracentric inversion of the long arm of chromosome 7 results in an in-frame fusion of the N-terminus of the A-kinase anchor protein 9 (exons 1-8) and the C-terminal catalytic domain (exons 9-18) of B-RAF. The resulting fusion protein has increased B-RAF kinase activity and is considerably active in NIH 3T3 focus formation assay and tumor formation in nude mice.…”

Impairment of the p27kip1 function enhances thyroid carcinogenesis in TRK-T1 transgenic mice

“…Furthermore, a novel oncogene, designated AKAP9-BRAF, deriving from the in-frame fusion of the first eight exons of the A-kinase anchor protein 9 (AKAP9) gene with the carboxyl-terminal encodingregion (exons 9-18) of BRAF, has been isolated from PTCs developed in irradiated patients after a short latency period (Ciampi et al 2005). As far as ras genes are concerned, mutations of codon 61 of N-RAS (N2) were significantly more frequent in follicular tumors (19%) than in papillary cancers (5%).…”