Ma.Tr.OC

Multiple Osteochondromas (MO) is an autosomal dominant disease characterized by the formation of multiple cartilage-capped bone tumors (osteochondromas, OCs) typically located at the meta-epiphyseal region of long bones. The most serious complication is malignant transformation of OCs into secondary peripheral chondrosarcomas (PCS). Even if MO is known to be principally caused by EXT1/EXT2 mutations – involved in heparan sulfate (HS) synthesis - it is not clear the mechanism of OC malignant transformation, leading to the difficulty in finding both potential therapeutic targets and optimized follow-up protocols. We hypothesize that differences in severity and, in particular, malignant degeneration, could be the result of alterations on different levels, from single nucleotide changes or copy number variations in modifier genes to epigenetic alterations and previous results prompted us to better investigate:
• The role of miRNAs in MO malignant transformation; our main hypothesis is that miRNA transcriptome profile could specifically change and that miRNAs and antagomirs could serve as therapeutic tools for the progression.
• Moreover we will investigate the mechanisms by which selected SNPs may affect MO clinical manifestations, with special focus on OCs malignant transformation into PCSs. Outputs of these studies will include the identification of SNP subsets associated with specific clinical manifestations, that may be used to identify young patients that will likely show severe phenotypes and, more importantly, subjects at higher risk of malignant PCS occurrence. To determine the presence of other genetic alterations that may be responsible for PCS development, our study will be completed by innovative Next Generation Whole Genome Sequencing experiments.
• Finally, to unravel the pathogenesis of malignant transformation, it is also important considering the biological basis of OC and PCS growth, evaluating HS status in malignant lesions, to then understand how eventually restore normal HS levels and treat the pathology. Actually, surgery is the only available treatment with several operations in patient lifespan and regular radiological screenings are the only preventive recommendation for MO patients. Aim of this study will be fulfill the lack of information related to OC malignant transformation in order to improve molecular and pathogenic knowledge about MO disease and find useful indications to unravel pathogenesis and patient treatment.

Multiple Osteochondromas (MO) is the most frequent rare dominant skeletal disorder characterized by the growth of several benign tumors (osteochondromas, OCs) potentially degenerating in malignancy (secondary peripheral chondrosarcoma, PCS). Even though MO is known to be caused by EXT1 and EXT2 mutations – involved in the heparan sulfate (HS) synthesis -, nothing is known about the mechanism responsible for malignant transformation, leading to difficulties in finding both potential therapeutic targets and optimized follow-up protocols. Integrating different European Research and Clinical Units, a comprehensive analysis of MO disease has been carried out with a specific focus on malignant degeneration. The largest clinically and genetically well annotated cohort of 1,663 patients has been collected by the Consortium, permitting to more accurately estimate the incidence of the malignancy (6.7%), its main clinical features, as well as the suggestion of some likely risk factors. A molecular mechanism potentially responsible for the growth of cartilaginous lesions in MO disease - also able to explain its high clinical variability and never assumed before – has been unraveled. For the first time, structural differences among OC, PCS, and healthy HS chains extracted from human cartilaginous excisions have been described, pointing out two macroscopic aspects of HS structures, i.e., the degree of sulfation and chain length, which appear to be significantly different in OC and PCS with respect to healthy cartilage; interestingly, it seems that HS structural analysis could be predictive of possible malignant degeneration of benign tumor. Moreover, several promising altered molecular pathways and genetics contributor typical for malignant tissues emerged by WGS and transcriptomic studies – whose implication has been confirmed in functional in vitro studies and so assuming a novel and highly significant role in MO progression. In conclusion, the results obtained in the MaTrOC project highlighted for the first time a series of peculiarities characterizing the malignant transformation compared to benign lesion, hypothesizing different potential approaches to restore the normal biological function, so representing a huge step forward and providing scientific basis for a future clinical approach.