The influence of the germline HSD3B1 adrenal-permissive variant (c.1100 C) on somatic alteration landscape, transcriptome, and immune-cell infiltration in prostate cancer

Authors:

Emmanuel S. Antonarakis, Shayan Nazari, Nicholas Zorko, Charles J. Ryan, Anna Prizment, Andrew Elliott, Chadi Nabhan, Pedro C. Barata, Rana R. McKay, Neeraj Agarwal, Nima Sharifi, Justin Hwang

Background: A missense-encoding germline polymorphism in the HSD3B1 gene has been shown to result in adrenal-permissive (c.1100 C, p.367 Thr) or adrenal-restrictive (c.1100 A, p.367 Asn) phenotypes with respect to androgen synthesis from adrenal precursors, and the adrenal-permissive variant is associated with inferior outcomes to hormonal therapies. However, the tumoral characteristics (somatic alteration landscape, transcriptome, immune-cell composition) of prostate cancers that arise in the context of these germline genotypes are unknown.

Methods: We utilized the Caris Life Sciences (Phoenix, AZ) database to study the relationship between germline HSD3B1 c.1100 genotypes and somatic tumoral characteristics in 5,421 prostate cancer biopsies. Germline HSD3B1 status was inferred using variant allele frequencies (VAFs) derived from tumor DNA sequencing: c.1100C VAF of 0% defined the AA genotype, VAF of 40-60% defined the AC genotype, and VAF of 100% defined the CC genotype. Each HSD3B1 genotype was interrogated for its associated mutational landscape (by exome sequencing) and tumor transcriptome (by RNA-seq); immune-cell subsets were explored using the quanTIseq deconvolution algorithm.

Results: The prevalence of the HSD3B1 c.1100 AA genotype (restrictive–homozygous) was 54.4%, AC (heterozygous) was 34.2%, and CC (permissive–homozygous) was 11.4%. Liver/lung metastases had the highest prevalence of the CC genotype (14.2%), while lymph node metastases had the lowest (10.9%). Among the ARassociated genes, compared to the AA genotype, the CC genotype had greater frequency of TMPRSS2-ERG fusions (35.5% vs 29.7%, P,0.01), AR-V7 (17.2% vs 14.7%, P=0.17), and mRNA expression of AR (median 124 vs 115 TPM, P=0.01), HOXB13 (37 vs 34 TPM, P=0.08) and KLK2 (490 vs 448 TPM, P=0.12); there were no associations with SPOP or FOXA1 mutations or expression. Outside of AR pathways, the MAPK activation signature was higher in the CC relative to the AA genotype (0.27 vs -0.04 MPAS, P=0.01). When examining immune-cell subsets and immunotherapy targets, the CC genotype unexpectedly showed higher CD276 (B7-H3) expression (30 vs 27 TPM, P,0.01), higher dendritic cells (P=0.02) and T-regs (P=0.03), and lower neutrophils (P=0.10) compared to the AA genotype.

Conclusions: The homozygous adrenal-permissive HSD3B1 variant (c.1100 CC) is associated with distinct tumoral features characterized by elevated AR signaling and MAPK activation. It is also associated with a unique immune-cell regulatory landscape, with higher B7-H3 expression, increased intratumoral dendritic cells and decreased immunosuppressive neutrophils. This distinct molecular landscape of HSD3B1 c.1100 CC–associated prostate cancers warrants special therapeutic considerations, including possibly using B7-H3–targeted therapies.