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.

Are we really at the dawn of understanding sporadic pediatric thyroid carcinoma?

“…BRAF fusions have also been described in postChernobyl thyroid cancer, suggesting that this is a new mechanism of BRAF activation in human cancers (Ciampi et al 2005, Ricarte-Filho et al 2013. As far as we known, AGK-BRAF fusion was described in a tumor from one radiation-exposed PTC case who was 13 years old at surgery (Ricarte-Filho et al 2013), while AKAP9-BRAF was identified in three tumors from radiation-exposed patients.…”

“…The overall prevalence of these other fusion transcripts was 6% in a pediatric radiation-exposed PTC range from 3% to 19% (Ciampi et al 2005, Sassolas et al 2012, Ricarte-Filho et al 2013 and 0% in sporadic (Ricarte-Filho et al 2013).…”

Molecular approaches to thyroid cancer diagnosis

“…BRAF is a serine-threonine kinase which, upon activation by RAS , activates MEK and leads to activation of downstream effectors of the MAPK pathway. In nearly all cases (98-99% of cases) activating point mutations of BRAF involve codon 600 and result in the V600E mutation, and in 1-2% of cases other BRAF mutations such as the K601E mutation, small in-frame insertions or deletions, or BRAF rearrangement can occur (Soares et al 2003; Ciampi, et al 2005; Ciampi and Nikiforov 2005; Hou, et al 2007b; Chiosea, et al 2009). …”

“…Fusion of BRAF with A kinase anchor protein 9 ( AKAP9 ) is a rearrangement rarely found in sporadic thyroid cancer, although it also occurs at higher frequencies (up to 11%) in patients with a history of radiation exposure (Ciampi et al 2005). NTRK1 is a receptor tyrosine kinase and when rearranged with one of 3 potential fusion partners, activates MAPK pathway signaling (Bongarzone, et al 1998; Musholt, et al 2000).…”

Thyroid Growth and Cancer

“…Nearly all the thyroid cancers that have been attributed to external or internal radiation have been papillary in type; where the oncogenes involved have been studied rearrangements in RET rather than point mutations in BRAF have been linked to radiation carcinogenesis [24,25]. Interestingly, a rare finding in short latency papillary carcinomas in children exposed to Chernobyl fallout is activation of BRAF by rearrangement [26]. …”