Nima Sharifi

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.

Association Between Adrenal-Restrictive HSD3B1 Inheritance and Hormone-Independent Subtypes of Endometrial and Breast Cancer

Abstract Background The germline variant rs1047303 (HSD3B1[1245A/C]), restricting or enabling production of potent androgens and estrogens from adrenal precursors, affects outcomes of castration-resistant prostate cancer and is associated with estrogen receptor positivity in postmenopausal breast cancer. Like breast cancer, endometrial cancer is another malignancy with hormone-dependent and hormone-independent subtypes. We hypothesized that adrenal-restrictive HSD3B1 genotype would associate with hormone-independent cancer subtypes. Methods We employed a previously described classification of tumors in The Cancer Genome Atlas into genomic clusters. We determined HSD3B1 genotype frequencies by endometrial cancer genomic cluster and calculated the odds per adrenal-restrictive A allele for the largely hormone-independent copy-number (CN) high subtype vs other subtypes. An equivalent analysis was performed for the genomically similar, hormone-independent basal breast cancer subtype. Last, we performed survival analyses for UK Biobank participants with endometrial cancer by HSD3B1 genotype. All statistical tests were 2-sided. Results The adrenal-restrictive HSD3B1(1245A) allele was associated with the CN-high endometrial cancer subtype (odds ratio [OR] = 1.63, 95% confidence interval [CI] = 1.14 to 2.32; P = .007). Similarly, HSD3B1(1245A) was associated with the basal breast cancer subtype (OR = 1.54, 95% CI = 1.13 to 2.08; P = .006). In the UK Biobank, endometrial cancer patients homozygous for HSD3B1(1245A) had worse overall (hazard ratio [HR] = 1.39, 95% CI = 1.16 to 1.68; P < .001) and cancer-specific (HR = 1.39, 95% CI = 1.14 to 1.70; P = .001) survival, consistent with the A allele being enriched in the more aggressive CN-high subtype. Conclusions These findings suggest roles for adrenal-restrictive vs adrenal-permissive steroidogenesis, by way of rs1047303 genotype, in the development of and/or outcomes from at least 3 commonly hormone-associated types of cancer: prostate, breast, and endometrial.