Exploring the complexity of Schwannomatosis: the role of LZTR1 and the molecular framework of schwannomatosis-associated schwannomas

Schwannomatosis (SCH) predisposes to multiple schwannomas, caused by mutations in two genes on 22q: SMARCB1 and LZTR1. A 4-hit mechanism, involving SMARCB1, LZTR1 and NF2, brings to development of SCH-related tumors. SMARCB1 shows a clearly define role in schwannomatosis, with a peculiar association of specific mutations with the development of meningiomas. Frequency of LZTR1 mutations is about 50 and 30% in familial and sporadic cases, respectively and we demonstrated that the type of LZTR1 mutation is related to protein expression in SCH-associated tumors. However, the remarkable defect of penetrance described for LZTR1 in schwannomatosis, associated to its involvement in Noonan syndrome and the unexpected high frequency of loss of function mutations in healthy population, suggest that its involvement should be consider carefully. In order to clarify the pathogenesis of schwannomatosis we characterized the tumor samples of our collection to obtain a molecular framework of schwannomatosis-associated schwannomas. The WES analysis does not identified common genes shared by different tumors from the same or different patients, except for NF2. Even the gene expression analysis did not highlight a clear correlation between expression patterns and common clinical features. The collected data demonstrated the peculiarity of schwannomatosis-associated schwannomas, for which NF2 somatic mutations seem to be the fundamental event addressing to schwannomas development. Schwannomatosis remains a complex disease, whose trigger molecular event and subsequent tumor pathogenesis are yet to be completely clarified.