Genomic Database Analysis of Uterine Leiomyosarcoma Mutational Profile

Uterine Leiomyosarcoma (uLMS) is by far the most common type of uterine sarcoma, characterized by an aggressive clinical course, a heterogeneous genetic profile and a very scarce response to cytotoxic chemotherapy. The genetic make-up of uLMS is an area of active study that could provide essential cues for the development of new therapeutic approaches. A total of 216 patients with uLMS from cBioPortal and AACR-GENIE databases were included in the study. The vast majority of patients (81%) carried at least one mutation in eitherTP53,RB1,ATRXorPTEN. The most frequently mutated gene wasTP53, with 61% of the patients harboring at least one mutation, followed byRB1at 48%.PTENalteration was more frequent in metastases than in primary lesions, consistent with a later acquisition during tumor progression. There was a significant trend forTP53andRB1mutations to occur together, while bothTP53andRB1were mutually exclusive with respect toCDKN2A/Binactivation. Overall survival did not show significant correlation with the mutational status, even ifRB1mutation emerged as a favorable prognostic factor in theTP53-mutant subgroup. This comprehensive analysis shows that uLMS is driven almost exclusively by the inactivation of tumor suppressor genes and suggests that future therapeutic strategies should be directed at targeting the main genetic drivers of uLMS oncogenesis.