Genetics of Ollier disease and Maffucci syndrome

The main purpose of the studies described in this thesis is to find the genetic deficit in Ollier disease and Maffucci syndrome. They are very rare, non-inherited syndromes with a unilateral predominance of the multiple enchondromas. Enchondroma is a benign cartilage forming tumor which can undergo malignant transformation towards chondrosarcoma. We hypothesized the presence of somatic mosaicism with an early post zygotic mutation. We used genome-wide and hypothesis driven approach to identify genes causing Ollier disease and Maffucci syndrome. Ultimately, we identified mutations in two genes (IDH1 and IDH2) that were present in the majority of the tumors from patients with Ollier disease and Maffucci syndrome. A subgroup of patients did not show mutations in IDH1, IDH2 or PTH1R and therefore, other genes (except ACP5, PTPN11, PTHLH, GNAS, NDST1) might be involved. Moreover, one can not exclude the possibility of functional links or pathways shared between IDH1 or IDH2 with EXT1, EXT2, PTH1R, PTPN11, PTHLH, TET2 and ACP5. We have shown that IDH1 mutations are associated with hypermethylation and consequently downregulation of several genes. DLX5 was the most differentially methylated gene between enchondromas with, and without IDH1 mutations which was found in our study.MRC-Holland, Anna FondsUBL - phd migration 201

Somatic mosaic IDH1 and IDH2 mutations are associated with enchondroma and spindle cell hemangioma in Ollier disease and Maffucci syndrome

Ollier disease and Maffucci syndrome are non-hereditary skeletal disorders characterized by multiple enchondromas (Ollier disease) combined with spindle cell hemangiomas (Maffucci syndrome). We report somatic heterozygous mutations in IDH1 (c.394C>T encoding an R132C substitution and c.395G>A encoding an R132H substitution) or IDH2 (c.516G>C encoding R172S) in 87% of enchondromas (benign cartilage tumors) and in 70% of spindle cell hemangiomas (benign vascular lesions). In total, 35 of 43 (81%) subjects with Ollier disease and 10 of 13 (77%) with Maffucci syndrome carried IDH1 (98%) or IDH2 (2%) mutations in their tumors. Fourteen of 16 subjects had identical mutations in separate lesions. Immunohistochemistry to detect mutant IDH1 R132H protein suggested intraneoplastic and somatic mosaicism. IDH1 mutations in cartilage tumors were associated with hypermethylation and downregulated expression of several genes. Mutations were also found in 40% of solitary central cartilaginous tumors and in four chondrosarcoma cell lines, which will enable functional studies to assess the role of IDH1 and IDH2 mutations in tumor formation

Genetics of Ollier disease and Maffucci syndrome

The main purpose of the studies described in this thesis is to find the genetic deficit in Ollier disease and Maffucci syndrome. They are very rare, non-inherited syndromes with a unilateral predominance of the multiple enchondromas. Enchondroma is a benign cartilage forming tumor which can undergo malignant transformation towards chondrosarcoma. We hypothesized the presence of somatic mosaicism with an early post zygotic mutation. We used genome-wide and hypothesis driven approach to identify genes causing Ollier disease and Maffucci syndrome. Ultimately, we identified mutations in two genes (IDH1 and IDH2) that were present in the majority of the tumors from patients with Ollier disease and Maffucci syndrome. A subgroup of patients did not show mutations in IDH1, IDH2 or PTH1R and therefore, other genes (except ACP5, PTPN11, PTHLH, GNAS, NDST1) might be involved. Moreover, one can not exclude the possibility of functional links or pathways shared between IDH1 or IDH2 with EXT1, EXT2, PTH1R, PTPN11, PTHLH, TET2 and ACP5. We have shown that IDH1 mutations are associated with hypermethylation and consequently downregulation of several genes. DLX5 was the most differentially methylated gene between enchondromas with, and without IDH1 mutations which was found in our study

Genetic characterization of mesenchymal, clear cell, and dedifferentiated chondrosarcoma

Molecular tumour pathology - and tumour genetic

Maffucci Syndrome: A Genome-Wide Analysis Using High Resolution Single Nucleotide Polymorphism and Expression Arrays on Four Cases

Ollier disease and Maffucci syndrome are rare, nonhereditary skeletal disorders characterized by the presence of multiple enchondromas with (Maffucci) or without (Ollier) co-existing multiple hemangiomas of soft tissue. Enchondromas can progress toward central chondrosarcomas. PTHIR mutations are found in a small subset of Ollier patients. The genetic deficit in Maffucci syndrome is unknown. Here, we report the first genome-wide analysis using Affymetrix SNP 6.0 array on Maffucci enchondromas (n = 4) and chondrosarcomas (n = 2) from four cases. Results were compared to a previously studied cohort of Ollier patients (n = 37). We found no loss of heterozygosity (LOH) or common copy number alterations shared by all enchondromas, with the exception of some copy number variations. As expected, chondrosarcomas were found to have multiple genomic imbalances. This is similar to conventional solitary and Ollier-related enchondromas and chondrosarcomas and supports the multistep genetic progression model. Expression profiling using Illumina BeadArray-v3 chip revealed that cartilaginous tumors in Maffucci patients are more similar to such tumors in Ollier patients than to sporadic cartilage tumors. Point mutations in a single gene or other copy number neutral genomic changes might play a role in enchondromagenesis. (C) 2011 Wiley-Liss, Inc.Molecular tumour pathology - and tumour genetic

Genome-wide analysis of Ollier disease: Is it all in the genes?

Background: Ollier disease is a rare, non-hereditary disorder which is characterized by the presence of multiple enchondromas (ECs), benign cartilaginous neoplasms arising within the medulla of the bone, with an asymmetric distribution. The risk of malignant transformation towards central chondrosarcoma (CS) is increased up to 35%. The aetiology of Ollier disease is unknown. Methods: We undertook genome-wide copy number and loss of heterozygosity (LOH) analysis using Affymetrix SNP 6.0 array on 37 tumours of 28 Ollier patients in combination with expression array using Illumina BeadArray v3.0 for 7 ECs of 6 patients. Results: Non-recurrent EC specific copy number alterations were found at FAM86D, PRKG1 and ANKS1B. LOH with copy number loss of chromosome 6 was found in two ECs from two unrelated Ollier patients. One of these patients also had LOH at chromosome 3. However, no common genomic alterations were found for all ECs. Using an integration approach of SNP and expression array we identified loss as well as down regulation of POU5F1 and gain as well as up regulation of NIPBL. None of these candidate regions were affected in more than two Ollier patients suggesting these changes to be random secondary events in EC development. An increased number of genetic alterations and LOH were found in Ollier CS which mainly involves chromosomes 9p, 6q, 5q and 3p. Conclusions: We present the first genome-wide analysis of the largest international series of Ollier ECs and CS reported so far and demonstrate that copy number alterations and LOH are rare and non-recurrent in Ollier ECs while secondary CS are genetically unstable. One could predict that instead small deletions, point mutations or epigenetic mechanisms play a role in the origin of ECs of Ollier disease.Optimising joint reconstruction management in arthritis and bone tumour patient

R132C IDH1 Mutations Are Found in Spindle Cell Hemangiomas and Not in Other Vascular Tumors or Malformations

Molecular tumour pathology - and tumour genetic

R132C IDH1 Mutations Are Found in Spindle Cell Hemangiomas and Not in Other Vascular Tumors or Malformations

MTG

R132C IDH1 Mutations Are Found in Spindle Cell Hemangiomas and Not in Other Vascular Tumors or Malformations

Molecular tumour pathology - and tumour genetic