Department of Pathology, University of California at San Francisco, San Francisco, CA, 94143, USA.
Department of Pathology, University of California at San Francisco, 1825 4Th Street, Room M2354, San Francisco, CA, 94158, USA.
Head Neck Pathol. 2023 Sep;17(3):722-730. doi: 10.1007/s12105-022-01523-9. Epub 2023 Mar 16.
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.
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.
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.
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.
颅面骨骨化性纤维瘤（OF）是一种纤维骨性病变，其特征是在细胞纤维母细胞基质中有各种形式的骨形成。OF 的分子特征尚不清楚。OF 存在一些已知的致病性异常，包括传统 OF 中的 HRPT2 突变和少年沙粒状 OF 中的 SATB2 易位。另一方面，关于 OF 中的 MDM2 基因扩增和染色体拷贝数改变（CNA）存在相互矛盾的报道。
从 OF 患者的手术切除活检和刮除标本中获得组织。回顾肿瘤的临床、放射学和病理学特征。从肿瘤组织的福尔马林固定、石蜡包埋块中提取基因组 DNA。针对 529 个癌症基因和选择内含子的编码区进行基于捕获的 DNA 下一代测序。
我们从 8 名男性和 8 名女性患者中鉴定出 17 例 OF，平均年龄为 22 岁（范围 1-58 岁）。9 例发生在颌骨，8 例发生在颌外颅面骨。这些病例包括 3 例少年沙粒状 OF、6 例传统 OF 和 8 例少年小梁状 OF。17 例中有 6 例存在大规模 CNA。7 例（41%）存在局灶性扩增，包括 FOSB（n=2，11%）、FOS（n=4，23%）、COL1A1（n=4，23%）和 TBX3（n=5，29%）。3 例（17%）存在致病性 CDC73 突变。没有病例显示局灶性 MDM2 扩增。
在这里，我们对 OF 进行了全面的分子特征分析，揭示了一种具有偶发性大规模 CNA（n=6，35%）的异质性遗传特征。调节 AP-1 转录复合物的 FOS、FOSB 和 TBX3 基因在 OF 中经常发生改变（n=7，41%），主要在少年小梁状 OF 中。这些基因编码作为 MAP 激酶信号通路下游效应物的转录因子。MDM2 扩增在 OF 中极为罕见，如果存在，也应继续引起对低度颌骨骨肉瘤的关注。总之，我们的研究结果表明，OF 在遗传水平上代表了一组异质性肿瘤，但 AP-1 通路的失调可能在少年小梁状 OF 的发病机制中发挥作用。
