TY - JOUR
T1 - Classification of Fibro-osseous Tumors in the Craniofacial Bones using DNA Methylation and Copy Number Alterations
AU - Kleijn, Tony G
AU - Ameline, Baptiste
AU - Schreuder, Willem H
AU - Szuhai, Károly
AU - Kooistra, Wierd
AU - van Kempen, Léon
AU - Japalagh, Ghazaleh S H
AU - Briaire-de Bruijn, Inge H
AU - van der Meeren, Stijn W
AU - Kleijwegt, Maarten C
AU - Witjes, Max
AU - Pichardo, Sarina E C
AU - van Furth, Wouter R
AU - Lausová, Tereza
AU - Breimer, Gerben E
AU - Braunius, W Weibel
AU - de Lange, Jan
AU - van Langevelde, Kirsten
AU - Kroon, Herman M
AU - van den Hout, Mari F C M
AU - Koppes, Sjors A
AU - Haefliger, Simon
AU - Ooft, Marc L
AU - van Engen-van Grunsven, Ilse C H
AU - Flucke, Uta E
AU - Hiemcke-Jiwa, Laura
AU - Savci-Heijink, Dilara C
AU - Diercks, Gilles F H
AU - Doff, Jan J
AU - Suurmeijer, Albert J H
AU - Bovée, Judith V M G
AU - von Deimling, Andreas
AU - Baumhoer, Daniel
AU - Cleven, Arjen H G
PY - 2025/6
Y1 - 2025/6
N2 - Fibro-osseous tumors of the craniofacial bones are a heterogeneous group of lesions comprising cemento-osseous dysplasia (COD), cemento-ossifying fibroma (COF), juvenile trabecular ossifying fibroma (JTOF), psammomatoid ossifying fibroma (PsOF), fibrous dysplasia (FD), and low-grade osteosarcoma (LGOS) with overlapping clinicopathological features. However, their clinical behavior and treatment differ significantly, underlining the need for accurate diagnosis. Molecular diagnostic markers exist for subsets of these tumors, including GNAS mutations in FD, SATB2 fusions in PsOF, mutations involving the RAS-MAPK signaling pathway in COD, and MDM2 amplification in LGOS. Because DNA methylation and copy number profiling are well established for the classification of central nervous system tumors, we aimed to investigate whether this tool might be used as well for classifying fibro-osseous tumors in the craniofacial bones. We collected a well-characterized, multicenter cohort with available molecular data, including COD (n = 20), COF (n = 13), JTOF (n = 10), PsOF (n = 25), FD (n = 23), LGOS (n = 4), and high-grade osteosarcoma (HGOS; n = 11). Genome-wide DNA methylation and copy number variation data were generated using the Illumina Infinium Methylation EPIC array interrogating >850 000 CpG sites. DNA methylation profiling yielded evaluable results in 73/106 tumors, including 6 CODs, 12 COFs, 6 JTOFs, 19 PsOFs, 18 FDs, 2 LGOSs, and 10 HGOSs. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) revealed that FD, extragnatic PsOF, and HGOS formed distinct clusters. Surprisingly, COD, COF, JTOF, and mandibular PsOF clustered together, apart from other craniofacial bone tumors. LGOS did not form a distinct cluster, likely due to the low number of cases. Copy number analysis revealed that FD, COD, COF, JTOF, and PsOF were typically characterized by flat copy number profiles compared with LGOS with gains of chromosome 12 and HGOS with multiple heterogeneous copy number alterations. In conclusion, using DNA methylation and copy number profiles, benign fibro-osseous tumors can be separated from low-grade and HGOSs in the craniofacial bones, which is of diagnostic value in challenging cases with overlapping clinicopathological features.
AB - Fibro-osseous tumors of the craniofacial bones are a heterogeneous group of lesions comprising cemento-osseous dysplasia (COD), cemento-ossifying fibroma (COF), juvenile trabecular ossifying fibroma (JTOF), psammomatoid ossifying fibroma (PsOF), fibrous dysplasia (FD), and low-grade osteosarcoma (LGOS) with overlapping clinicopathological features. However, their clinical behavior and treatment differ significantly, underlining the need for accurate diagnosis. Molecular diagnostic markers exist for subsets of these tumors, including GNAS mutations in FD, SATB2 fusions in PsOF, mutations involving the RAS-MAPK signaling pathway in COD, and MDM2 amplification in LGOS. Because DNA methylation and copy number profiling are well established for the classification of central nervous system tumors, we aimed to investigate whether this tool might be used as well for classifying fibro-osseous tumors in the craniofacial bones. We collected a well-characterized, multicenter cohort with available molecular data, including COD (n = 20), COF (n = 13), JTOF (n = 10), PsOF (n = 25), FD (n = 23), LGOS (n = 4), and high-grade osteosarcoma (HGOS; n = 11). Genome-wide DNA methylation and copy number variation data were generated using the Illumina Infinium Methylation EPIC array interrogating >850 000 CpG sites. DNA methylation profiling yielded evaluable results in 73/106 tumors, including 6 CODs, 12 COFs, 6 JTOFs, 19 PsOFs, 18 FDs, 2 LGOSs, and 10 HGOSs. Unsupervised clustering and dimensionality reduction (Uniform Manifold Approximation and Projection) revealed that FD, extragnatic PsOF, and HGOS formed distinct clusters. Surprisingly, COD, COF, JTOF, and mandibular PsOF clustered together, apart from other craniofacial bone tumors. LGOS did not form a distinct cluster, likely due to the low number of cases. Copy number analysis revealed that FD, COD, COF, JTOF, and PsOF were typically characterized by flat copy number profiles compared with LGOS with gains of chromosome 12 and HGOS with multiple heterogeneous copy number alterations. In conclusion, using DNA methylation and copy number profiles, benign fibro-osseous tumors can be separated from low-grade and HGOSs in the craniofacial bones, which is of diagnostic value in challenging cases with overlapping clinicopathological features.
KW - DNA methylation
KW - cemento-osseous dysplasia
KW - copy number alterations
KW - craniofacial bones
KW - fibro-osseous tumor
KW - fibrous dysplasia
KW - ossifying fibroma
KW - osteosarcoma
U2 - 10.1016/j.modpat.2025.100717
DO - 10.1016/j.modpat.2025.100717
M3 - Article
SN - 0893-3952
VL - 38
JO - Modern Pathology
JF - Modern Pathology
IS - 6
M1 - 100717
ER -