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

## TL;DR

This study shows how a specific HSD3B1 gene variant affects tumor behavior and clinical outcomes in breast and endometrial cancers, particularly in relation to menopausal status.

## Contribution

The study reveals novel associations between HSD3B1 genotypes and distinct tumor characteristics in breast and endometrial cancers, influenced by menopausal status.

## Key findings

- Premenopausal ER+ breast tumors with CC genotype show enrichment in hormone-related pathways.
- Premenopausal triple-negative breast tumors with AA genotype have elevated immune and epithelial gene expression and more MED12 alterations.
- Endometrioid EC CC tumors show suppression of immune and proliferative pathways.

## Abstract

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.