Andrew Elliott

HSD3B1 (c.1100C) Genotype Is Associated with Distinct Tumoral and Clinical Outcomes in Breast and Endometrial Cancers

HSD3B1 encodes an enzyme that catalyzes the conversion of adrenal precursors into potent sex steroids. A common germline variant (c.1100C) enhances this effect and is linked to breast cancer (BC) progression. As the HSD3B1 genotypes contribute to differences in local and adrenal steroid production, their transcriptional and phenotypic effects on cancers influenced by hormonal signaling such as BC and endometrial cancer (EC)—particularly in relation to menopausal status—remain unclear. We analyzed BC and EC sequenced from patients that received diagnostic tests in oncology clinics, and we determined the germline HSD3B1 c.1100 genotype (AA, AC, CC) from tumor DNA sequencing by using variant allele frequency, with inferred menopausal status assumed by age at molecular profiling. Whole-transcriptome RNA sequencing and gene set enrichment analysis showed that adrenal-permissive homozygous (CC) tumors in premenopausal ER + BC were enriched for hormone-related pathways, including Estrogen Response Early (NES ≈ +1.8). In premenopausal triple-negative BC, adrenal-restrictive homozygous (AA) tumors exhibited the elevated expression of immune and epithelial genes and the increased prevalence of MED12 alterations (AA 0.25% vs. CC 8%, p < 0.01). In endometrioid EC, CC tumors demonstrated the suppression of immune and proliferative pathways. Postmenopausal cases had higher progesterone receptor IHC positivity (AA 75% vs. CC 83%, p < 0.05) and numerically more frequent ESR1 copy number gains (AA 2.0% vs. CC 4.0%). Results highlight context-specific associations between germline HSD3B1 genotypes and tumor biology in BC and EC.

Large-Scale Multiomic Analysis Identifies Anatomic Differences and Immunogenic Potential in Subtypes of Leiomyosarcoma

Abstract Purpose: Comprehensive molecular profiling was used to define the genomic and immune landscapes of leiomyosarcomas (LMS) by anatomic subtypes, which have not been completely characterized. Experimental Design: A total of 1,115 LMS samples, categorized into uterine LMS (uLMS), retroperitoneal LMS, or other LMS (oLMS), underwent DNA/RNA sequencing (Caris Life Sciences). Genomic/transcriptomic profiles were compared across subtypes. Immune profiling was compared with melanoma (n = 1,255), an immunogenic tumor. Insurance claims data were used to infer real-world outcomes with immune checkpoint inhibitors (ICI) in LMS. Results: uLMSs (n = 701) were molecularly distinct from retroperitoneal LMSs (n = 166) and oLMSs (n = 248). RB1 mutations and MAP2K4 copy-number amplification were more common in non-uLMS. MED12 mutations were almost exclusive to uLMS. Traditional ICI response biomarkers (i.e., PD-L1) did not vary by anatomic site. Non-uLMS demonstrated upregulated immune-related gene sets, including IFN and inflammatory response pathways, and higher immune cell infiltration, especially CD8+ T cells and B cells (>2-fold increase, P < 0.0001). LMS had lower immune cell abundance and T cell–inflamed scores (TIS) compared with melanoma, though 11% of oLMS samples had high TIS scores. In a real-world cohort (n = 138), 29% of patients with LMS receiving ICI were treated >6 months, indicating potential clinical benefit. Conclusions: Comprehensive profiling suggested that uLMS represents a molecularly distinct disease from non-uLMS. Although traditional ICI response biomarkers were similar across anatomic subtypes, uLMSs were immune cold compared with non-uLMS. Signals for ICI responsiveness, such as high TIS and immune cell abundance, in some tumors suggest that further research into immunotherapies for LMS is warranted.