Interrogating the Genomic Landscape of Uterine Leiomyosarcoma: A Potential for Patient Benefit

Abstract

Uterine leiomyosarcoma (uLMS) is a rare and aggressive gynaecological malignancy. Surgical removal and chemotherapy are commonly used to treat uLMS, but recurrence rates are high. Over the last few decades, clarification of the genomic landscape of uLMS has revealed a number of recurring mutations, including TP53, RB1, ATRX, PTEN, and MED12. Such genomic aberrations are difficult to target therapeutically or are actively targeted in other malignancies, and their potential as targets for the treatment of uLMS remains largely unexplored. Recent identification of deficiencies in homologous recombination in a minority of these tumours, however, has provided a rationale for investigation of PARP inhibitors in this sub-set. Here, we review these mutations and the evidence for therapeutic avenues that may be applied in uLMS. We also provide a comprehensive background on diagnosis and current therapeutic strategies as well as reviewing preclinical models of uLMS, which may be employed not only in testing emerging therapies but also in understanding this challenging and deadly disease.

A Deep Multi-Omics Integration Approach Reveals New Molecular Features of Uterine Leiomyosarcoma

“…First, our ndings are in accordance with others when characterizing biomarkers in uLMS including HRD, low TMB, low MSI, and features of immunologically cold tumors (5,6,9,10,21).…”

“…In recent years, the identi cation of variants has emerged as a promising avenue for identifying novel diagnostic and therapeutic targets in uLMS (5,6). Characterizing the molecular landscape of uLMS is essential for the development of targeted therapies, but the molecular underpinnings of this tumor are complex and the identi cation of actionable targets is challenging (7)(8)(9)(10).…”

“…This heterogeneity complicates the identi cation of driver mutations and therapeutic targets. The uLMS genome is characterized by dispersed large ampli cations and deletions, with gains of up to 15% and losses of up to 45% of the genome (3,5,8,12). The aneuploidy of uLMS is also related to chromothripsis, a random catastrophic genome instability event that is overrepresented in sarcomas (13,14).…”

Targeting homologous recombination deficiency in uterine leiomyosarcoma

“…RNA sequencing has also identified frequent fusion genes disrupting multiple tumour suppressor genes, such as RB1, TP53, ATRX, DAXX, CAMTA1, SETD2 and KDM5CA [ 14 ]. Currently, none of these aberrations are routinely targeted therapeutically in individuals with uLMS [ 18 ] and thus treatment strategies continue unchanged and disease outcomes have remained stagnant for decades.…”

“…Unlike individuals with other gynaecological malignancies, who are typically referred to familial genetics clinics for germline BRCA1/2 testing, individuals with uLMS are not routinely screened for such germline mutations in the clinic, although some individuals with uLMS have been shown to carry germline mutations in TP53 or RB1 [ 18 ], albeit at a low rate (below the internationally accepted cut off of ~ 10% prevalence for germline mutations in the target population requiring testing [ 27 ]). In their reanalysis of the TCGA and GENIE soft-tissue sarcoma datasets, in addition to their own uLMS cohort, Seligson and associates observed that alterations in BRCA1/2 , concluded to be somatic, were significantly more common in uLMS compared with non-uterine LMS (10% compared to 1%, respectively, p -value 0.02, n = 61 patients) [ 28 ].…”