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.