Vobugari Nikitha, Makovec Allison, Kellen Samuel, Nazari Shayan S, Elliott Andrew, Schmeck Devin, Deacon Aiden, von Dohlen Gabriella, John Emily, Barata Pedro C, Agarwal Neeraj, Geller Melissa A, Erickson Britt K, Sledge George, Ostrander Julie H, McKay Rana R, Ryan Charles J, Sharifi Nima, Antonarakis Emmanuel S, Hwang Justin
Department of Medicine, University of Minnesota-Twin Cities, Minneapolis, MN 55455, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN 55455, USA.
Int J Mol Sci. 2025 Jun 14;26(12):5720. doi: 10.3390/ijms26125720.
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 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 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 alterations (AA 0.25% vs. CC 8%, < 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%, < 0.05) and numerically more frequent copy number gains (AA 2.0% vs. CC 4.0%). Results highlight context-specific associations between germline genotypes and tumor biology in BC and EC.
编码一种催化肾上腺前体转化为强效性类固醇的酶。一种常见的种系变异（c.1100C）增强了这种作用，并与乳腺癌（BC）进展相关。由于这些基因型导致局部和肾上腺类固醇生成存在差异，它们对受激素信号影响的癌症（如BC和子宫内膜癌（EC））的转录和表型影响——特别是与绝经状态相关的影响——仍不清楚。我们分析了在肿瘤诊所接受诊断测试的患者的BC和EC序列，并通过使用变异等位基因频率从肿瘤DNA测序中确定种系c.110基因型（AA、AC、CC），根据分子谱分析时的年龄推断绝经状态。全转录组RNA测序和基因集富集分析表明，绝经前雌激素受体阳性（ER +）BC中的肾上腺允许性纯合（CC）肿瘤富含激素相关途径，包括早期雌激素反应（标准化富集分数≈ +1.8）。在绝经前三阴性BC中，肾上腺限制性纯合（AA）肿瘤表现出免疫和上皮基因表达升高以及改变的患病率增加（AA为0.25%，CC为8%，P < 0.01）。在子宫内膜样EC中，CC肿瘤表现出免疫和增殖途径的抑制。绝经后病例的孕激素受体免疫组化阳性率更高（AA为75%，CC为83%，P < 0.05），并且在数量上拷贝数增加更频繁（AA为2.0%，CC为4.0%）。结果突出了种系基因型与BC和EC中肿瘤生物学之间的背景特异性关联。
