The Influence of the Germline HSD3B1 Adrenal-Permissive Allele (c.1100 C) on the Somatic Alteration Landscape, the Transcriptome, and Immune Cell Infiltration in Prostate Cancer

<b>Background/Objectives</b>: The germline polymorphism in the <i>HSD3B1</i> gene (c.1100 C) results in adrenal-permissive (CC) or adrenal-restrictive (AA) functions of the protein product by regulating the production of high-affinity ligands that activate androgen signaling. Prior studies have indicated that the CC genotype is associated with worse response to hormonal therapies in prostate cancer (PC) patients. <b>Methods</b>: To characterize the impact of germline <i>HSD3B1</i> variants on somatic tumor features, we examined 6550 primary and metastatic PCs from the Caris Life Sciences database, in which the genomic and transcriptomic landscapes were acquired via paired whole-exome/whole-transcriptome sequencing. <b>Results</b>: The overall prevalence of the <i>HSD3B1</i> AA genotype (restrictive-homozygous) was 48.8%, AC (permissive-heterozygous) was 32.8%, and CC (permissive-homozygous) was 14.9%. There was enrichment of the CC genotype in these PC patients as compared to prior reports that examined non-cancerous populations. However, the rates of the CC genotype varied between metastatic site and by race. Compared to the AA genotype, tumors harboring the CC genotype did not demonstrate increased <i>AR</i> alterations, nor higher expression of <i>AR</i>, <i>FOXA1</i>, <i>HOXB13</i>, or AR signaling signatures. We instead found significant changes in immune-associated hallmark pathways, immune cell fractions, and biomarkers that inform the use of immune therapies (TMB-high, MSI-high). Further, the CC and AA genotypes exhibited notable differences in the expression of immunoglobulins, MHC class I/II molecules, and cell surface targets. The differences in expression by <i>HSD3B1</i> genotype were especially notable in lung and liver metastases. <b>Conclusions</b>: Our study indicates that in prostate cancers, <i>HSD3B1</i> germline c.1100 allele status may not directly influence tumor-intrinsic genomics but is associated with novel functions beyond androgen signaling.