Recurrent rearrangements of FOS and FOSB define osteoblastoma

Abstract

The transcription factor FOS has long been implicated in the pathogenesis of bone tumours, following the discovery that the viral homologue, v-fos, caused osteosarcoma in laboratory mice. However, mutations of FOS have not been found in human bone-forming tumours. Here, we report recurrent rearrangement of FOS and its paralogue, FOSB, in the most common benign tumours of bone, osteoblastoma and osteoid osteoma. Combining whole-genome DNA and RNA sequences, we find rearrangement of FOS in five tumours and of FOSB in one tumour. Extending our findings into a cohort of 55 cases, using FISH and immunohistochemistry, provide evidence of ubiquitous mutation of FOS or FOSB in osteoblastoma and osteoid osteoma. Overall, our findings reveal a human bone tumour defined by mutations of FOS and FOSB.

An update of molecular pathology of bone tumors. Lessons learned from investigating samples by next generation sequencing

“…Notably, the previously reported loss of 22q was not detected . Otherwise, the genomes revealed few and insignificant alterations in terms of SNVs and copy number aberrations …”

“…Until recently, molecular data on osteoid osteoma and osteoblastoma were scarce . However, analysis of whole genome and RNA‐sequencing of five osteoblastomas and one osteoid osteoma revealed that all tumors showed an oncogenic structural rearrangement in the AP‐1 transcription factor, either FOS on chromosome 14, or, in one case, its paralogue FOSB on chromosome 19 . Notably, the previously reported loss of 22q was not detected .…”

“…Notably, the rearrangements did not involve the coding sequence of other genes ( KIAA1199 , MYO1B , and ANK ) and in the two remaining cases the fusion partner did not lie within a gene. Indeed, the vast majority of cases with FOS rearrangements that were detected by fluorescence in situ hybridization (FISH) were strongly immunoreactive for FOS using an antibody against the N terminus …”

“…1,2 Otherwise, the genomes revealed few and insignificant alterations in terms of SNVs and copy number aberrations. 3 Remarkably, the FOS break points were all exonic, residing within a narrow genomic locus of exon 4, and the rearrangements included both interchromosomal and intrachromosomal events. Notably, the rearrangements did not involve the coding sequence of other genes (KIAA1199, MYO1B, and ANK) and in the two remaining cases the fusion partner did not lie within a gene.…”

Immunohistochemical correlates of recurrent genetic alterations in sarcomas

“…The FOS family of proteins (including FOSB, FOS, FOSL1, and FOSL2) each partner with JUN to form a heterodimer and act as a transcription factor complex, known as AP‐1. FOSB shows recurrent rearrangement in two endothelial tumor types, pseudomyogenic hemangioendothelioma (PHE) and epithelioid hemangioma; FOSB fusions were also recently reported in osteoblastoma . PHE (also known as epithelioid sarcoma‐like hemangioendothelioma) is a rare neoplasm of intermediate biological potential, first described in 1992 (originally believed to be an epithelioid sarcoma variant), which is more common in males and characteristically presents in a multicentric fashion in different tissue planes of the involved limb.…”