DNA methylation profile discriminates sporadic giant cell granulomas of the jaws and cherubism from their giant cell-rich histological mimics. DNA methylation profile discriminates sporadic giant cell granulomas of the jaws and cherubism from their giant cell-rich histological mimics

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, the latter occurring exclusively in the central form. Less commonly, multiple giant cell lesions can develop in the context of syndromes such as cherubism, which is an autosomal dominant bone disease. Morphologically, giant cell granulomas can closely resemble other giant cell-rich lesions such as non-ossifying fibroma and aneurysmal bone cyst, and to a minor extent giant cell tumour of bone and chondroblastoma. The epigenetic basis of these giant cell-rich tumours is unclear and, recently, DNA methylation profile has been shown to be clinically useful for the diagnosis of other tumour types, including brain tumours as well as bone and soft tissue sarcomas. Therefore, we aimed to assess the DNA methylation profile of central and peripheral sporadic giant cell granulomas of the jaws and cherubism to test whether DNA methylation patterns can help to distinguish these entities. Additionally, we further compared the DNA methylation profile of these lesions with those of other giant cell-rich mimics to investigate if the microscopic similarities extend to the epigenetic level. Our results showed that central and peripheral sporadic giant cell granulomas of the jaws and cherubism share a related DNA methylation pattern with that of peripheral sporadic giant cell granulomas and cherubism appearing slightly distinct, while central sporadic giant cell granulomas show overlap with both of the former. Non-ossifying fibroma, aneurysmal bone cyst, giant cell tumour of bone, and chondroblastoma, on the other hand, have distinct methylation patterns. Therefore, DNA methylation profiling is currently not capable of clearly distinguishing sporadic and cherubism-associated giant cell lesions of the jaws. Conversely, it could discriminate sporadic giant cell granulomas from their giant cell-rich mimics. Overall design: retrospective study of archival FFPE tissues

颌骨巨细胞肉芽肿常散发性单发，表现为中心性或外周性病变。其特征为携带KRAS、FGFR1或TRPV4体细胞突变，其中TRPV4突变仅见于中心性病变。少数情况下，多种巨细胞病变可并发于如巨颌症（cherubism）这类常染色体显性遗传性骨病的背景中。形态学上，颌骨巨细胞肉芽肿可与多种富含巨细胞的病变高度相似，如非骨化性纤维瘤、动脉瘤样骨囊肿，在一定程度上还与骨巨细胞瘤、软骨母细胞瘤相似。目前这类富含巨细胞肿瘤的表观遗传学基础尚不明确，而近年研究显示DNA甲基化谱（DNA methylation profile）对包括脑肿瘤、骨与软组织肉瘤在内的多种肿瘤类型的临床诊断具有实用价值。因此，本研究旨在分析颌骨散发性中心性、外周性巨细胞肉芽肿及巨颌症的DNA甲基化谱，以验证甲基化模式是否有助于区分这些病变实体。此外，本研究还将上述病变的甲基化谱与其他巨细胞性鉴别病变的甲基化谱进行比对，以探究显微镜下的形态相似性是否在表观遗传层面同样存在。研究结果显示，颌骨散发性中心性巨细胞肉芽肿、散发性外周性巨细胞肉芽肿与巨颌症的DNA甲基化谱具有相关性，其中散发性外周性巨细胞肉芽肿与巨颌症的甲基化谱略具差异，而散发性中心性巨细胞肉芽肿则与二者均存在重叠。而非骨化性纤维瘤、动脉瘤样骨囊肿、骨巨细胞瘤及软骨母细胞瘤则具有截然不同的甲基化谱。综上，当前DNA甲基化谱分析尚无法明确区分颌骨散发性与巨颌症相关性巨细胞病变，但可有效区分颌骨散发性巨细胞肉芽肿与其富含巨细胞的鉴别诊断病变。整体研究设计：对存档福尔马林固定石蜡包埋（FFPE）组织的回顾性研究。