Background/Objectives: The germline polymorphism in theHSD3B1gene (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.Methods: To characterize the impact of germlineHSD3B1variants 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.Results: The overall prevalence of theHSD3B1AA 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 increasedARalterations, nor higher expression ofAR,FOXA1,HOXB13, 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 byHSD3B1genotype were especially notable in lung and liver metastases.Conclusions: Our study indicates that in prostate cancers,HSD3B1germline c.1100 allele status may not directly influence tumor-intrinsic genomics but is associated with novel functions beyond androgen signaling.
背景/目的：HSD3B1基因的种系多态性（c.1100 C）通过调控激活雄激素信号通路的高亲和力配体的产生，导致其蛋白产物呈现肾上腺许可型（CC）或肾上腺限制型（AA）功能。既往研究表明，CC基因型与前列腺癌患者对激素治疗反应较差相关。方法：为明确种系HSD3B1变异对体细胞肿瘤特征的影响，我们分析了Caris生命科学数据库中6550例原发性和转移性前列腺癌样本，这些样本通过配对全外显子组/全转录组测序获取了基因组和转录组图谱。结果：HSD3B1 AA基因型（限制型-纯合子）总体占比为48.8%，AC基因型（许可型-杂合子）为32.8%，CC基因型（许可型-纯合子）为14.9%。与既往针对非癌人群的研究报告相比，这些前列腺癌患者中CC基因型比例有所富集。然而，CC基因型比例在不同转移部位和种族间存在差异。与AA基因型相比，携带CC基因型的肿瘤并未显示AR改变增加，也未表现出AR、FOXA1、HOXB13或AR信号通路特征基因表达升高。相反，我们发现了免疫相关标志通路、免疫细胞组分以及指导免疫治疗应用的生物标志物（TMB-high、MSI-high）的显著变化。此外，CC与AA基因型在免疫球蛋白、MHC I/II类分子及细胞表面靶点的表达上呈现显著差异。这种由HSD3B1基因型导致的表达差异在肺和肝转移灶中尤为明显。结论：本研究提示在前列腺癌中，HSD3B1种系c.1100等位基因状态可能不直接影响肿瘤内在基因组特征，而是与雄激素信号通路之外的新功能相关。
肿瘤(癌症)患者之家