FAM131B-BRAF Fusion Gene Resulting From 7q34 Deletion Leads to MAPK Pathway Activation in Pilocytic Astrocytoma

Pilocytic astrocytoma (PA, WHO Grade I) is the most common childhood brain tumor, accounting for approximately 20% of brain tumors in childhood. Recently, we and others have shown that tandem duplication at 7q34, resulting in KIAA1549-BRAF fusion genes and constitutive activation of the MAPK signaling pathway, is a hallmark genetic lesion in PA development. Alternative mechanisms of MAPK activation include BRAF and KRAS point mutations, RAF1 fusions, and Neurofibromatosis-associated NF1 mutations. To elucidate underlying genetic driver alterations leading to aberrant MAPK activation, we screened 125 primary tumors for mutations in KRAS, NRAS, PTPN11, BRAF and RAF1 and performed multiplex and long-distance inverse (LDI) PCR to identify BRAF and RAF1 fusion genes. To define the mechanism underlying the formation of novel BRAF fusion genes and understand their phenotype, we used microarray-based comparative genomic hybridization (aCGH) and performed in vitro experiments for functional assessment. Fusions targeting RAF kinases were found in 72% (90/125) of cases. Sequencing confirmed all previously reported variants of KIAA1549-BRAF and yielded novel variants of this fusion gene and of SRGAP3-RAF1 . Mutations in KRAS and BRAF , as well as RAF1 gene fusions were mostly mutually exclusive with BRAF rearrangements. Most importantly, we identified FAM131B as an alternative fusion partner of BRAF , resulting from an interstitial deletion of ˜2.5 Mb at 7q34, in 3 cases. Investigating the functional characteristics of FAM131B-BRAF, we demonstrated constitutive MEK phosphorylation and activation of MAPK downstream effectors. Furthermore, we showed that FAM131B-BRAF is able to transform NIH3T3 cells. Our results implicate RAF kinase fusions as a central oncogenic mechanism in PA tumor development and strengthen their potential role both as a tumor-specific marker for the molecular diagnosis of PA and as an ideally suited target for molecular therapeutic intervention.

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