MDM2 Gene Amplification and Expression of MDM2 and CDK4 are Rare in Ossifying Fibroma of Craniofacial Bones

Abstract

Ossifying fibroma of the craniofacial bones is a fibro-osseous lesion characterized by varied patterns of bone formation in a fibroblastic stroma. Ossifying fibroma is a putatively benign lesion with no reports of malignant transformation or metastasis. Differentiation from other fibro-osseous lesions can be challenging necessitating synthesis of clinical, radiological and pathological findings. The molecular pathogenesis of ossifying fibroma is poorly understood but recent studies have reported MDM2 gene amplification and chromosomal copy number changes in a subset of ossifying fibromas. MDM2 amplification in ossifying fibroma, if true, presents a diagnostic problem because this genetic event, at least among craniofacial fibro-osseous lesions, was previously considered specific for low-grade osteosarcoma. In the present study, we investigated the utility of MDM2 and CDK4 immunohistochemistry, and fluorescence in situ hybridization for MDM2 gene amplification, in the diagnosis of 44 craniofacial bone ossifying fibromas. Focal MDM2 and CDK4 nuclear immunoreactivity was found in 11 and 1 ossifying fibromas, respectively, but none demonstrated MDM2 amplification by fluorescence in situ hybridization. A single tumor displayed MDM2 amplification without nuclear immunoreactivity to either MDM2 or CDK4. Our data suggest that while focal MDM2 and CDK4 nuclear expression may be detected in a minority of ossifying fibromas, this expression does not correlate with MDM2 amplification. In addition, MDM2 amplification is extremely rare in ossifying fibroma so the detection of this genetic abnormality should continue to raise concern for osteosarcoma.

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

“…Focal MDM2 amplification was not identified in any case though case 7 showed gain of MDM2 secondary to tetrasomy of chromosome 12. The only case (case 6) that showed MDM2 amplification by FISH in our prior study [13] did not display MDM2 amplification by NGS in the current analysis. This discrepancy is difficult to explain.…”

“…[7]. A separate study using FISH demonstrated MDM2 amplification in only 2% of OF without concordant protein overexpression [13]. Similar conflicting results were also reported in the copy number profiles of OF; whereas some studies showed large-scale CNAs, others showed none [12,16].…”

“…The diagnoses were based on light microscopic, radiographic, and clinical features. Except for case 15, all cases were previously reported [13].…”

“…The cohort consisted of 6 conventional/cemento-OF, 3 JPOF and 8 JTOF. MDM2 and CDK4 expression and MDM2 amplification status reported in our prior study [13] are included in Table 1 to allow direct comparison to the current data. We were unable to perform NGS on the remaining 27 cases from the prior study due to insufficient tissue or DNA yield.…”

“…CNA-associated genes with amplified expression included MDM2 and CDK4 by qPCR [12]. Conversely, we recently demonstrated that MDM2 gene amplification and MDM2 and CDK4 protein overexpression are exceptionally rare in OF by fluorescent in situ hybridization (FISH) and by immunohistochemistry, respectively [13]. Little is known about gene rearrangements in OF.…”