The landscape of chromosomal instability in uterine leiomyosarcoma.

5607 Background: Uterine leiomyosarcoma (uLMS) has heterogeneous clinical presentations and outcomes. Although most uLMSs are associated with chromosomal instability, limited data exist on chromosomal instability patterns and their association with clinical outcomes. We sought to examine the chromosomal and genomic landscape of uLMSs and their association with survival outcomes. Methods: We identified 162 patients with uLMS who underwent matched tumor-normal next-generation sequencing at our institution between 2007 and 2024. Allele-specific copy number analysis was performed using the FACETS algorithm with genome-wide summary data as well as focal copy number data extracted and compared with clinical variables and survival outcomes. Appropriate statistical analyses were performed. Results: The median age at diagnosis was 55 years (range, 30-92). The uLMS in the cohort predominantly had conventional spindle cell morphology (n=122/162, 75%). At the time of diagnosis, 42% presented as FIGO stage I disease (68/162) followed by FIGO stage IV disease (60/162, 37%). ER expression data was available for 155 cases, with the majority of cases being ER positive (106/155, 68%). PR expression data was available for 145 cases, with most of the tumors expressing PR (87/145, 60%). The most common alterations in the cohort were TP53 (117, 72%), RB1 (78, 48%), ATRX (62, 38%), and PTEN (31, 19%). FACETS analysis showed that 15% of tumors (25/162) were hypoploid and 12% had whole-genome duplication (20/162). The median telomeric size was 50.1 Mb (interquartile range [IQR]: 40-59.3). The median number of telomeric allele imbalances was 6 (IQR: 3-9). The median fraction of genome with loss of heterozygosity was 0.28 (IQR: 0.14-10.5). Centromeric allele imbalance, whole-genome duplication, and fraction of copy number altered were associated with ER expression (adjusted P=0.025, 0.015, and 0.002, respectively). Multivariate survival analysis demonstrated that hypoploidy (hazard ratio: 3.3) and copy number alterations in PIK3CD (hazard ratio: 1.82) were associated with worse overall survival (P<0.001 for both). Conclusions: Although most uLMSs are caused by underlying chromosomal instability, the patterns in these tumors are variable, with some of the chromosomal instability configurations having prognostic implications. Further studies are needed to better understand the role of chromosomal instability in the stratification of the disease.