FOS/FOSB rearrangements; defining the human bone tumour, osteoblastoma
Session type: Poster / e-Poster / Silent Theatre session
Osteoblastoma, and the related entity osteoid osteoma, are the most common benign bone-forming tumours. Large, inaccessible, and recurrent tumours can cause considerable morbidity. On occasion, there can be diagnostic uncertainty with osteosarcoma, a malignant tumour that requires multi-modal therapy. We sought to define the somatic changes that underpin osteoblastoma.
We analysed the transcriptome and whole genomes of 5 osteoblastomas and 1 osteoid osteoma and catalogued all somatic variants. FOS fusions were validated with Sanger sequencing. We used FISH and Immunohistochemistry (IHC) to validate the finding of FOS/FOSB rearrangements in 55 osteoblastomas, 17 angiosarcomas and 183 osteosarcomas. We analysed 55 osteosarcoma and 2652 pan-cancer whole genomes for similar rearrangements.
Amidst a paucity of somatic alterations, analysis of structural variants revealed breakpoints in the AP-1 transcription factor FOS in 5/6 cases(Fig.1), and its paralogue FOSB in the sixth case(Fig.2). All were validated with RNA-seq reads and FOS fusions were validated with Sanger sequencing.
FOSB fusion brought expression under the control of the PPP1R10 promotor. FOS fusions were all between exon 4 and intronic or intergenic regions. FOS fusions resulted in the introduction of a stop codon within 30bp of the breakpoint.
In a validation cohort of 55 tumours, FISH identified FOSB or FOS breakapart signals in 1 and 48 tumours respectively (89%). IHC for the preserved N-terminus of FOS revealed marked immunoreactivity in all FOS rearranged cases, including the 3/6 FOS FISH negative cases with available material. Only 1/183 osteosarcoma cases had comparable FOS immunoreactivity. No osteosarcoma or pan-cancer whole genome harboured similar rearrangements.
We suggest that FOS or FOSB rearrangements define osteoblastoma and osteoid osteoma. The truncated FOS transcript and protein bears a striking resemblance to the retroviral oncogenic form of v-fos, known to induce osteosarcoma in mice. This is the first report of FOS alteration in a bone-forming tumour.