In situ metabolomics of aldosterone-producing adenomas
In situ metabolomics of aldosterone-producing adenomas
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DOI：
10.1172/jci.insight.130356
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发表时间：
2019-09-05
期刊：
影响因子：
8
通讯作者：
Beuschlein, Felix
中科院分区：
文献类型：
--
作者：
Murakami, Masanori;Rhayem, Yara;Beuschlein, Felix
最近的遗传学检查和多种类固醇谱为醛固酮腺瘤(APA)的亚型提供了基础。本研究的目的是制作一张全面的、高分辨率的APAs与形态测量、免疫组织化学图谱、突变状态和临床结果之间的关系的质谱图。研究队列包括136名单侧原发性醛固酮增多症患者。进行基质辅助激光解吸/电离-傅里叶变换-离子回旋共振MSI，并利用基因/表型信息分析代谢物谱，包括来自形态计量学的数字图像分析和类固醇生成酶的IHC。在Ken‘s和CACNAID突变的APAs之间观察到明显的分子特征，137种代谢物有显著差异，包括嘌呤代谢和类固醇合成的代谢物。肿瘤内18-氧皮质醇和18-羟基皮质醇的浓度与CyP11B1的染色强度呈负相关。CYP11B1的染色强度较低和18-氧皮质醇水平较高与手术后临床完全成功的可能性较高。本研究显示了不同代谢类型的APAs与肿瘤基因的关系。此外，我们揭示了皮质醇衍生物和CYF11B1之间的负相关以及18-氧皮质醇和CYP11B1对临床结果的影响，这为APAs的病理生理、临床特征和类固醇的发生提供了前所未有的见解。
Recent genetic examinations and multisteroid profiles have provided the basis for subclassification of aldosterone-producing adenomas (APAs). The objective of the current study was to produce a comprehensive, high-resolution mass spectrometry imaging (MSI) map of APAs in relation to morphometry, immunohistochemical profiles, mutational status, and clinical outcome. The study cohort comprised 136 patients with unilateral primary aldosteronism. Matrix-assisted laser desorption/ionization-Fourier transform-ion cyclotron resonance MSI was conducted, and metabolite profiles were analyzed with genotype/phenotype information, including digital image analysis from morphometry and IHC of steroidogenic enzymes. Distinct molecular signatures between KEN'S- and CACNAID-mutated APAs with significant differences of 137 metabolites, including metabolites of purine metabolism and steroidogenesis, were observed. Intratumor concentration of 18-oxocortisol and 18-hydroxycortisol were inversely correlated with the staining intensity of CYP11B1. Lower staining intensity of CYP11B1 and higher levels of 18-oxocortisol were associated with a higher probability of complete clinical success after surgery. The present study demonstrates distinct metabolomic profiles of APAs in relation to tumor genotype. In addition, we reveal an inverse correlation between cortisol derivatives and CYF11B1 and the impact of 18-oxocortisol and CYP11B1 on clinical outcome, which provides unprecedented insights into the pathophysiology, clinical features, and steroidogenesis of APAs.