title: Common somatic alterations identified in maffucci syndrome by molecular karyotyping.
abstract: Maffucci syndrome (MS) is a rare congenital disorder characterized by multiple central cartilaginous tumors (enchondromas) in association with cutaneous spindle cell hemangiomas. These patients have a high incidence of malignant transformation. No familial case is known and the etiopathogenic cause remains unknown. In enchondromatosis (Ollier disease, OD), which is comprised of enchondromas only, 4 mutations in the PTHR1 gene have been identified in 4 patients; 3 were somatic and 1 was germline. No PTHR1 mutations have been detected in MS, whereas somatic IDH1 and, more rarely, IDH2 mutations have been observed in 77% of patients with MS and 81% of patients with OD. These genetic alterations are shared with other tumors, including glioma, leukemia and carcinoma. To search for underlying somatic genomic causes, we screened MS tissues using Affymetrix SNP-chips. We looked for CNVs, LOH and uniparental isodisomy (UPID) by performing pairwise analyses between allelic intensities in tumoral DNA versus the corresponding blood-extracted DNA. While common chromosomal anomalies were absent in constitutional DNA, several shared CNVs were identified in MS-associated tumors. The most frequently encountered somatic alterations were localized in 2p22.3, 2q24.3 and 14q11.2, implicating these chromosomal rearrangements in the formation of enchondromas and spindle cell hemangiomas in MS. In one chondrosarcoma specimen, large amplifications and/or deletions were observed in chromosomes 3, 6, 9, 10, 12, 13, and 19. Some of these genetic changes have been reported in other chondrosarcomas suggesting an etiopathogenic role. No LOH/UPID was observed in any Maffucci tissue. Our findings identify frequent somatic chromosomal rearrangements on 2p22.3, 2q24.3 and 14q11.2, which may unmask mutations leading to the lesions pathognomonic of MS.
authors.affiliation: Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Mustapha
authors.initials: M
authors.lastname: Amyere
authors.affiliation: Department of Dermatology, Université de Caen Basse Normandie, CHU Caen, Caen, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Dompmartin
authors.affiliation: Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium.
authors.forename: Vinciane
authors.initials: V
authors.lastname: Wouters
authors.affiliation: Consultation des Angiomes, Hôpital Lariboisière, Paris, France.
authors.forename: Odile
authors.initials: O
authors.lastname: Enjolras
authors.affiliation: Department of Clinical Genetics, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: Ilkka
authors.initials: I
authors.lastname: Kaitila
authors.affiliation: Division of Orthopedic Surgery, Division of Plastic Surgery, Cliniques Universitaires St-Luc, Brussels, Belgium.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Docquier
authors.affiliation: Laboratory of Pathology, Division of Plastic Surgery, Cliniques Universitaires St-Luc, Brussels, Belgium.
authors.forename: Catherine
authors.initials: C
authors.lastname: Godfraind
authors.affiliation: Department of Plastic and Oral Surgery, Children's Hospital and Harvard Medical School, Boston, Mass., USA.
authors.forename: John Butler
authors.initials: JB
authors.lastname: Mulliken
authors.affiliation: Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium ; Center for Vascular Anomalies, Division of Plastic Surgery, Cliniques Universitaires St-Luc, Brussels, Belgium.
authors.forename: Laurence Myriam
authors.initials: LM
authors.lastname: Boon
authors.affiliation: Laboratory of Human Molecular Genetics, de Duve Institute, Université catholique de Louvain, Brussels, Belgium ; Walloon Excellence in Lifesciences and Biotechnology (WELBIO), Université catholique de Louvain, Brussels, Belgium.
authors.forename: Miikka
authors.initials: M
authors.lastname: Vikkula
keywords: Cancer; Chondrosarcoma; Copy number variation; Defect; Enchondroma; Enchondromatosis; Gene; Microarray; Mutation; Spindle cell hemangiomas