Estudo do perfil de metilação do DNA dos granulomas esporádicos de células gigantes dos maxilares, do querubismo e de seus mimetizadores histológicos

Abstract

Giant cell granulomas of the jaws often occur sporadically as single central or peripheral lesions. They are characterized by KRAS, FGFR1, or TRPV4 somatic mutations, being the latter exclusive of the central lesions. Less commonly, they may be multiple and associated with cherubism, an autosomal dominant bone disease. The diagnosis based on microscopy alone can be challenging. These jaw lesions share histopathological features with other giant cell-rich lesions: non-ossifying fibroma of bone, aneurysmal bone cyst, giant cell tumor of bone, and chondroblastoma. The epigenetic basis of these giant cell-rich tumors is unclear and recently DNA methylation profile has been shown to be clinically useful for the diagnosis of other tumor types, including pediatric brain tumors as well as sarcomas. Therefore, we aimed at assessing the DNA methylation profile of central and peripheral sporadic giant cell granulomas of the jaws and cherubism to test if DNA methylation patterns can help distinguish these entities. Additionally, we further compared their DNA methylation profile with those of their giant cell rich mimics to investigate if the microscopic similarities extend to the epigenetic level. DNA methylation analysis was performed for central (n = 10) and peripheral (n = 10) giant cell granulomas, cherubism (n = 6), non-ossifying fibroma (n = 10), aneurysmal bone cyst (n = 16), giant cell tumor of bone (n = 9), and chondroblastoma (n = 10) using the Infinium Human Methylation EPIC BeadChip. Furthermore, based on the DNA methylation data, copy number analysis was conducted. Central and peripheral sporadic giant cell granulomas and cherubism share a related DNA methylation pattern, with those of peripheral granulomas and cherubism appearing slightly distinct while central granuloma shows overlap with both of the former. The global and enhancer-associated DNA methylation values showed a similar distribution pattern among the groups, with cherubism showing the lowest median value of the mean methylation β-values and peripheral giant cell granuloma showing the highest value. In contrast, promoter regions showed a different methylation distribution pattern, with cherubism showing the highest median value compared to sporadic giant cell granulomas. None of the samples included in the study exhibited a consistent pattern regarding gains or losses of chromosomal arms or segments. In conclusion, DNA methylation profiling is currently not capable of clearly distinguishing sporadic and cherubism-associated giant cell granulomas of the jaws. Conversely, it could discriminate sporadic giant cell granulomas of the jaws from their giant cell-rich mimics.