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

: The germline polymorphism in the 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. : To characterize the impact of germline 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. : The overall prevalence of the 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 alterations, nor higher expression of , , , 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 genotype were especially notable in lung and liver metastases. : Our study indicates that in prostate cancers, germline c.1100 allele status may not directly influence tumor-intrinsic genomics but is associated with novel functions beyond androgen signaling.