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.