Background: Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy with a high mortality and poor prognosis. To elucidate the genetic underpinnings of ACCs, we have analyzed the transcriptome profiles of ACC tumor samples from patients enrolled in the TCGA and NCI cohorts. Methods: We developed a bimodal approach using Gaussian Mixture Models to identify genes with bimodal distribution in ACC samples. Among the 72 bimodally expressed genes that are used to stratify patients into prognostic groups, we focused onSEMA7A, as it encodes a glycosylphosphatidylinositol-anchored membrane glycoprotein (Semaphorin 7a) regulating integrin-mediated signaling, cell migration and immune responses. Results: Our findings reveal that high expression levels ofSEMA7Agene are associated with poor prognosis (hazard ratio = 4.27;p-value < 0.001). In hormone-producing ACCs,SEMA7Aexpression is elevated and positively correlated with genes driving steroidogenesis, aldosterone and cortisol synthesis, includingCYP17A1,CYP11A1,INHA,DLK1,NR5A1andMC2R. Correlation analyses show thatSEMA7Ais co-expressed with theintegrin-β1,FAK(focal adhesion kinase) andMAPK/ERK(mitogen-activated protein kinase/extracellular signal regulated kinases) signaling pathways. Immunohistochemistry (IHC) staining demonstrates the feasibility of evaluatingSEMA7Ain ACC tissues and shows a significant correlation between gene expression (RNA-Seq) and protein expression (IHC). Conclusions: These findings suggestSEMA7Aas a candidate for further research in ACC biology and a candidate for cancer therapy, as well as a potential prognosis biomarker for ACC patients.
背景：肾上腺皮质癌（ACC）是一种罕见且侵袭性强的内分泌恶性肿瘤，具有高死亡率和不良预后。为阐明ACC的遗传基础，我们分析了来自TCGA和NCI队列患者ACC肿瘤样本的转录组谱。方法：我们开发了一种基于高斯混合模型的双峰分析方法，以识别在ACC样本中呈双峰分布的基因。在用于将患者分层为预后组的72个双峰表达基因中，我们重点关注SEMA7A基因，该基因编码一种糖基磷脂酰肌醇锚定膜糖蛋白（Semaphorin 7a），可调节整合素介导的信号传导、细胞迁移和免疫反应。结果：我们的研究发现，SEMA7A基因的高表达水平与不良预后相关（风险比=4.27；p值<0.001）。在激素分泌型ACC中，SEMA7A表达升高，并与驱动类固醇生成、醛固酮和皮质醇合成的基因（包括CYP17A1、CYP11A1、INHA、DLK1、NR5A1和MC2R）呈正相关。相关性分析显示，SEMA7A与整合素-β1、FAK（黏着斑激酶）以及MAPK/ERK（丝裂原活化蛋白激酶/细胞外信号调节激酶）信号通路共表达。免疫组织化学（IHC）染色证明了在ACC组织中评估SEMA7A的可行性，并显示基因表达（RNA-Seq）与蛋白表达（IHC）之间存在显著相关性。结论：这些发现表明，SEMA7A可作为ACC生物学进一步研究和癌症治疗的候选靶点，并可能成为ACC患者的潜在预后生物标志物。
肿瘤(癌症)患者之家