Genomic Profiling of the Craniofacial Ossifying Fibroma by Next-Generation Sequencing - PubMed (original) (raw)

Genomic Profiling of the Craniofacial Ossifying Fibroma by Next-Generation Sequencing

Dorukhan H Bahceci et al. Head Neck Pathol. 2023 Sep.

Abstract

Background: Ossifying fibroma (OF) of the craniofacial skeleton is a fibro-osseous lesion characterized by various patterns of bone formation in a cellular fibroblastic stroma. The molecular landscape of OF remains mostly unknown. There are a few known pathogenic abnormalities in OF, including HRPT2 mutations in conventional OF and SATB2 translocations in juvenile psammomatoid OF. On the other hand, conflicting reports exist regarding MDM2 gene amplification and chromosomal copy number alterations (CNA) in OF.

Methods: Surgically removed biopsies and curettage specimens from OF patients were obtained. Clinical, radiographic, and pathologic features of tumors were reviewed. Genomic DNA was extracted from formalin-fixed, paraffin-embedded blocks of tumor tissue. Capture-based DNA next-generation sequencing targeting the coding regions 529 cancer genes and select introns was performed.

Results: We identified 17 OF cases from 8 male and 8 female patients with mean age of 22 years (range 1-58 years). Nine case occurred in the gnathic bones and 8 in the extragnathic craniofacial bones. These cases included 3 juvenile psammomatoid OF, 6 conventional OF and 8 juvenile trabecular OF. Large-scale CNAs were present in 6 of 17 cases. Seven cases (41%) had focal amplifications including FOSB (n = 2, 11%), FOS (n = 4, 23%), COL1A1 (n = 4, 23%) and TBX3 (n = 5, 29%). Three cases (17%) had pathogenic CDC73 mutations. No cases showed focal MDM2 amplification.

Conclusions: Here, we provided a comprehensive molecular characterization of OF that reveals a heterogeneous genetic profile with occasional large-scale CNAs (n = 6, 35%). FOS, FOSB, and TBX3 genes that regulate AP-1 transcriptional complex are frequently altered in OF (n = 7, 41%), chiefly in juvenile trabecular OF. These genes encode transcription factors that act as downstream effectors of the MAP kinase signaling pathway. MDM2 amplification is an exceedingly rare event in OF, if present at all, so identification of this event should continue to raise concern for low-grade gnathic osteosarcoma. In summary, our findings suggest that OF represents a heterogeneous group of tumors at the genetic level but dysregulation of the AP-1 pathway may play a role in pathogenesis of juvenile trabecular OF.

Keywords: AP-1; MDM2; Next-generation sequencing; Ossifying fibroma.

© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.

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Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

Fig. 1

Fig. 1

Representative morphologic and radiographic findings of ossifying fibroma. A, C Juvenile psammomatoid ossifying fibroma (case 3) with a uniform distribution of psammomatoid bony metaplasia and intervening stroma of bland spindle cells and giant cells; central skull base mass centered within the sphenoid sinuses with gross expansion of all local structures and erosion of surrounding bones without invasion. B, D Conventional/cemento-ossifying fibroma (case 6) with low-grade dense cellular fibroblastic stroma that forms new bone; well-defined soft tissue mass in the right a mass centered in the right ethmoid bone with high density material which may be appears to invade the nasal septum, with extension into the left ethmoid sinus. C, E Juvenile trabecular ossifying fibroma (case 12) with cellular osteoid and woven bone in a trabecular pattern set in a variably cellular storiform to fascicular monotonous bland fibrous stroma; well-circumscribed mixed expansile bony lesions in the left maxilla causing bony remodeling and expansion of neighboring structures without aggressive radiologic characteristics

Fig. 2

Fig. 2

Genomic profiles of 17 ossifying fibromas highlighting recurrent alterations. Each row represents a gene and columns represent individual tumors

Fig. 3

Fig. 3

Representative copy number alterations of case 4 (A) and 7 (B)

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