title: A new subtype of high-grade mandibular osteosarcoma with RASAL1/MDM2 amplification.
abstract: In contrast to long bone osteosarcoma, mandibular osteosarcoma is highly heterogeneous and morphologically overlaps with benign tumors, obscuring diagnosis and treatment selection. Molecular characterization is difficult due to the paucity of available specimens of this rare disease. We aimed to characterize the spectrum of mandibular osteosarcoma using immunohistochemistry and molecular techniques (quantitative polymerase chain reaction and sequencing) and compare them with benign fibro-osseous lesions. Forty-nine paraffin-embedded mandible osteosarcoma tissue samples were collected retrospectively and compared with 10 fibrous dysplasia and 15 ossifying fibroma cases. These were analyzed for molecular markers thought to differ between the different diseases and subtypes: MDM2 (murine double-minute type 2) overexpression, GNAS (guanine nucleotide-binding protein/α subunit) mutations, and amplification of MDM2 and/or RASAL1 (RAS protein activator like 1). Five fibroblastic high-grade osteosarcoma subtypes showed MDM2 amplification, including 2 with a microscopic appearance of high-grade osteosarcoma with part low-grade osteosarcoma (differentiated/dedifferentiated osteosarcoma) and MDM2 overexpression. The other 3 contained a coamplification of MDM2 and RASAL1, a signature also described for juvenile ossifying fibroma, with no overexpression of MDM2. These were of the giant cell-rich high-grade osteosarcoma, with areas mimicking juvenile ossifying fibroma (ossifying fibroma-like osteosarcoma). Our results show that some diagnosed high-grade osteosarcomas are differentiated/dedifferentiated osteosarcomas and harbor an overexpression and amplification of MDM2. In addition, juvenile ossifying fibromas can potentially evolve into giant cell-rich high-grade osteosarcomas and are characterized by a RASAL1 amplification (osteosarcoma with juvenile ossifying fibroma-like genotype). Thus, the presence of a RASAL1 amplification in ossifying fibroma may indicate a requirement for closer follow-up and more aggressive management.
authors.affiliation: Department of Pathology, IUCT-Oncopole, 1 Av Irène Joliot-Curie, 31059 Toulouse Cedex 9, France; Institute of Pharmacology and Structural Biology, CNRS UMR5089, F-31077 Toulouse, France.
authors.forename: Maxime
authors.initials: M
authors.lastname: Guérin
authors.affiliation: Department of Radiation Oncology, Centre Lacassagne, 06200 Nice, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Thariat
authors.affiliation: Department of Statistical Analysis, IUCT-Oncopole, 31059 Toulouse Cedex 9, France.
authors.forename: Mounia
authors.initials: M
authors.lastname: Ouali
authors.affiliation: Department of Pathology, Hôpital de la Timone, 13385 Marseille Cedex 5, France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Bouvier
authors.affiliation: Department of Pathology, Centre Léon Bérard, 69008 Lyon, France.
authors.forename: Anne-Valérie
authors.initials: AV
authors.lastname: Decouvelaere
authors.affiliation: Department of Pathology, Hôtel-Dieu, 44093 Nantes Cedex 1, France.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Cassagnau
authors.affiliation: Department of Pathology, CHU Lilles, 59037 Lille Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Aubert
authors.affiliation: Department of Pathology, Hôpital Pellegrin, 33000 Bordeaux, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Lepreux
authors.affiliation: Department of Pathology, Institut Bergonié, 33076 Bordeaux Cedex, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Coindre
authors.affiliation: Department of Pathology, CHU Besançon, 25000 Besançon, France.
authors.forename: Séverine
authors.initials: S
authors.lastname: Valmary-Degano
authors.affiliation: Department of Pathology, Hôpital Cochin, APHP, 75014 Paris, France.
authors.forename: Frédérique
authors.initials: F
authors.lastname: Larousserie
authors.affiliation: Department of Pathology, IUCT-Oncopole, 1 Av Irène Joliot-Curie, 31059 Toulouse Cedex 9, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Meilleroux
authors.affiliation: Department of Pathology, IUCT-Oncopole, 1 Av Irène Joliot-Curie, 31059 Toulouse Cedex 9, France.
authors.forename: Fabrice
authors.initials: F
authors.lastname: Projetti
authors.affiliation: Department of Pathology, CHU Rennes, 35000 Rennes, France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Stock
authors.affiliation: Department of Pathology, Cliniques Universitaires Saint-Luc, 1200 Bruxelles, Belgium.
authors.forename: Christine
authors.initials: C
authors.lastname: Galant
authors.affiliation: Department of Pathology, CHU de Nancy, 54035 Nancy Cedex, France.
authors.forename: Béatrice
authors.initials: B
authors.lastname: Marie
authors.affiliation: Department of Pathology, Centre Lacassagne, 06189 Nice, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Peyrottes
authors.affiliation: Department of Pathology, CHU Tours, 37000 Tours, France.
authors.forename: Gonzague
authors.initials: G
authors.lastname: de Pinieux
authors.affiliation: Department of Pathology, IUCT-Oncopole, 1 Av Irène Joliot-Curie, 31059 Toulouse Cedex 9, France; Institute of Pharmacology and Structural Biology, CNRS UMR5089, F-31077 Toulouse, France. Electronic address: brouchet.anne@chu-toulouse.fr.
authors.forename: Anne
authors.initials: A
authors.lastname: Gomez-Brouchet
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D002454:Cell Differentiation; D002864:Chromogranins; D004252:DNA Mutational Analysis; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics; D020690:GTPase-Activating Proteins / Q000235:genetics*; D005784:Gene Amplification; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008339:Mandibular Neoplasms / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D009154:Mutation; D012516:Osteosarcoma / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D016133:Polymerase Chain Reaction; D011379:Prognosis; D051736:Proto-Oncogene Proteins c-mdm2 / Q000032:analysis / Q000235:genetics*; D012189:Retrospective Studies; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D002864:Chromogranins; D020690:GTPase-Activating Proteins; C580923:RASAL1 protein, human; C497206:MDM2 protein, human; D051736:Proto-Oncogene Proteins c-mdm2; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs
keywords: Bone tumor; MDM2; Molecular analysis; Ossifying fibroma; Osteosarcoma; RASAL1