Somatic loss of an EXT2 gene mutation during malignant progression in a patient with hereditary multiple osteochondromas.
Multiple osteochondromas (MO) is an autosomal-dominant skeletal disorder caused by mutations in the exostosin-1 (EXT1) or exostosin-2 (EXT2) genes. In this study, we report the analysis of the mutational status of the EXT2 gene in tumor samples derived from a patient affected by hereditary MO, documenting the somatic loss of the germline mutation in a giant chondrosarcoma and in a rapidly growing osteochondroma. The sequencing of all exons and exon-intron junctions of the EXT1 and EXT2 genes from blood DNA of the proband did not reveal any mutation in the EXT1 gene but did demonstrate the presence of the transition point mutation c.67C > T in the EXT2 gene, determining the introduction of a stop codon in the coding sequence (p.Arg23*). A mutational analysis of other members of the family and the presence of osteochondromas in the metaphysis of long bones confirmed the diagnosis of hereditary multiple osteochondromas. Direct sequencing from DNA extracted from different sites of two tumor samples (a small rapidly growing osteochondroma and a giant peripheral secondary chondrosarcoma, each located at different chondrocostal junctions) revealed the loss of the germline EXT2 mutation. Analysis of microsatellite polymorphic markers in the 11p region harboring the EXT2 gene did not reveal any loss of heterozygosity. This observation supports a recent model of sarcomagenesis in which osteochondroma cells bear EXT homozygous inactivation, whereas chondrosarcoma-initiating cells are EXT-expressing cells.
Scuola Superiore di Catania, University of Catania, Catania, Italy; Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Catania, Italy.
Nicolò
N
Musso
Dipartimento di Chirurgia Toracica, Centro Clinico e Diagnostico "G.B Morgagni", Catania, Italy.
Francesco Paolo
FP
Caronia
Dipartimento di Chirurgia Toracica, Centro Clinico e Diagnostico "G.B Morgagni", Catania, Italy; Department of Biomedical and Biotechnological Sciences, Section of Human Anatomy and Histology, University of Catania, Catania, Italy.
Sergio
S
Castorina
Department DICHIRONS, Università degli Studi di Palermo, University of Palermo, Palermo, Italy.
Attilio Ignazio
AI
Lo Monte
Scuola Superiore di Catania, University of Catania, Catania, Italy; Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Catania, Italy.
Vincenza
V
Barresi
Scuola Superiore di Catania, University of Catania, Catania, Italy; Department of Biomedical and Biotechnological Sciences, Section of Medical Biochemistry, University of Catania, Catania, Italy. Electronic address: daniele.condorelli@unict.it.
Daniele Filippo
DF
Condorelli
D000328:Adult; D001859:Bone Neoplasms / Q000235:genetics*; D002813:Chondrosarcoma / Q000235:genetics*; D002880:Chromosomes, Human, Pair 11; D004273:DNA, Neoplasm / Q000032:analysis; D018450:Disease Progression; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D009154:Mutation; D017351:N-Acetylglucosaminyltransferases / Q000235:genetics* / Q000502:physiology; D000099065:Exostosin 2; D000099058:Exostosin 1
D004273:DNA, Neoplasm; D017351:N-Acetylglucosaminyltransferases; D000099058:Exostosin 1; D000099065:Exostosin 2
Hereditary multiple osteochondromas; chondrosarcoma; hereditary cancer; tumor suppressor gene