Somatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that... Show moreSomatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1(R132H) mutations. Patients harbouring IDH1(R132H) mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations ("non-R132H IDH1/2 mutations"). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1(R132H) have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1(R132H) mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication. Show less
Non-ossifying fibroma (NOF) has been an intriguing entity since its first description. It is the most common bone tumour, is usually asymptomatic affecting children and adolescents, is composed of... Show moreNon-ossifying fibroma (NOF) has been an intriguing entity since its first description. It is the most common bone tumour, is usually asymptomatic affecting children and adolescents, is composed of a heterogeneous cell population, and undergoes spontaneous regression after puberty. In a recent article in The Journal of Pathology, Baumhoer and colleagues demonstrate mutations activating the RAS-MAPK pathway (KRAS, FGFR1 and NF1) in similar to 80% of the tumours. Activation of the RAS-MAPK pathway by somatic mutations is found in a plethora of tumour types, both benign and malignant, while germline mutations cause a wide range of syndromes collectively termed the RASopathies. Their findings indicate that NOF, for long thought to be reactive, should be considered a true neoplasm. Moreover, their data suggest that only a subset of cells in the lesion contain the mutation. A second cell population consisting of histiocytes and osteoclast-like giant cells appears to be reacbenign and locally aggressive bone tumours and seems essential for tumourigenesis. The spontaneous regtive. This intimate relation between WT and mutant cells is also frequently encountered in other ression remains enigmatic and it is tempting to speculate that pubertal hormonal signalling, especially increased oestrogen levels, affect the balance between mutant and WT cells. (c) 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. Show less
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... Show moreThe 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. Show less
Osteoarthritis (OA) is a prevalent and complex disorder with a high hereditary probability. Previous genetic research into OA has yielded several common gene variants contributing to joint... Show moreOsteoarthritis (OA) is a prevalent and complex disorder with a high hereditary probability. Previous genetic research into OA has yielded several common gene variants contributing to joint specific OA phenotypes. Only a few studies allowed an examination of multiple joint sites in the patients included. In this thesis, we have focused, on the identification and investigation of OA susceptibility of rare and common generalised OA (GOA) in family based studies and common OA in the population. We investigated previously reported relationships between two candidate genes (FRZB and MATN3) with OA in a random sample from the population-based Rotterdam study and in siblings from the Genetics Osteoarthritis and Progression (GARP) study. A functional variant in FRZB indeed associates to OA but this seems not confined to hip only. Associations of MATN3 variants suggest that genetic variation in this gene determines susceptibility to spinal disc degeneration and OA of the first carpometacarpal joint. Different linkage areas were identified for early and late onset GOA. We mapped a major locus for OA at multiple joint sites on 14q32.11 in middle aged siblings from the GARP study and on 2q33.3 in seven early onset families. From our studies so far, DIO2, IDH1 and NRP2 may be new OA loci. Show less
