Multiomic analysis to reveal distinct molecular profiles of uterine and nonuterine leiomyosarcoma.

11555 Background: Leiomyosarcoma (LMS) is a rare group of mesenchymal malignancies found in the uterus, retroperitoneum, skin, or other soft-tissue sites. Treatment for LMS is extrapolated from trials including both uterine (uLMS) and non-uLMS subtypes, although whether they respond similarly and have similar outcomes from treatment is not clear. We examined the molecular composition of LMS by site of origin to better inform future drug development and trial design. Methods: We reviewed 1115 specimens with LMS histology tested by Caris Life Sciences for targeted exome (NextSeq, 592 gene panel), whole exome, and whole transcriptome sequencing (NovaSeq). Specimens were stratified into uLMS, rpLMS (retroperitoneal), and otherLMS (non-uterine/retroperitoneal) subgroups based on tumor origin sites. Genomic data was analyzed for mutations, copy number aberrations, and fusions. RNA expression profiling included evaluation of individual genes and gene set enrichment analysis (GSEA). P-value adjustment performed by the Benjamini-Hochberg procedure. Results: The study cohort was comprised of 62.9% uLMS (n = 701), 14.9% rpLMS (n = 166) and 22.2% otherLMS (n = 248) specimens. Overall, LMS specimens most frequently harbored TP53 (64%, n = 612), ATRX (30%, n = 219), RB1 (22%, n = 156), and MED12 (16%, n = 94) mutations, with these genes accounting for 74.4% (n = 1044) of all observed pathogenic/likely pathogenic mutations. RB1 mutations were significantly less common in uLMS (15%) compared to rpLMS (30%, p < 0.05) and otherLMS (33%, p < 0.01), whereas MED12 mutations were almost exclusive to uLMS (22% vs 1% rpLMS, 3% otherLMS, p < 0.05). MAP2K4 copy number amplification were more common in rpLMS (22%, p < 0.001) and otherLMS (14%, p < 0.182) compared to uLMS (7%), with frequent co-amplification of nearby genes ( FLCN, GID4, SPECC1, GAS7, PER1, and AURKB) located at chr17p11-13. Actionable gene fusions involving ALK (2.1%, n = 11), FGFR1 (0.2%, n = 1), and NTRK1/2 (0.2%, n = 1 each) were rare overall, with similar prevalence across subtypes. Genomic alteration rates were not significantly different between rpLMS and otherLMS subtypes . RNA expression profiling identified significant upregulation of PI3K/AKT/mTOR, DDR, WNT/Beta-Catenin pathway genes in non-uLMS. GSEA indicated several immune-related gene sets were enriched in rpLMS and otherLMS compared to uLMS. Conclusions: Comprehensive molecular profiling suggests that LMS originating from the uterus represents a molecularly distinct disease compared to other primary sites of origin. We identified key genomic patterns which have potential for targeted therapy. These data provide insight for the framework of future clinical trials designed to separate uLMS from non-uLMS histologies, although further subdivision does not appear to be warranted.