Urine metabolomic analysis in clear cell and papillary renal cell carcinoma: A pilot study.,Journal of Proteomics

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Urine metabolomic analysis in clear cell and papillary renal cell carcinoma: A pilot study.
Journal of Proteomics ( IF 2.8 ) Pub Date : 2020-02-29 , DOI: 10.1016/j.jprot.2020.103723
Julia Oto ₁ , Álvaro Fernández-Pardo ₁ , Marta Roca ₂ , Emma Plana ₃ , Mª José Solmoirago ₁ , José V Sánchez-González ₄ , César D Vera-Donoso ₄ , Manuel Martínez-Sarmiento ₄ , Francisco España ₁ , Silvia Navarro ₁ , Pilar Medina ₁

Affiliation

Renal cell carcinoma (RCC) is one of the most lethal type of tumors and is twice more frequent in men than in women. Initial symptoms are unspecific and belated thus increasing mortality. Moreover, current diagnostic and monitoring tools are harmful for the patient and unspecific in low-grade tumors. Therefore, novel minimally-invasive markers are needed to diagnose and monitor RCC patients. Urine represents the ideal sample source of non-invasive biomarkers for RCC. In our study we aimed to identify a urine metabolomic profile characteristic of RCC patients with diagnostic purposes and also to identify a profile with prognostic value. By an UPLC-Q-ToF MS untargeted metabolomic analysis, we compared the metabolomic profile of 23 RCC patients (14 clear cell RCC and 9 papillary RCC) before surgery and that of 23 healthy controls. Additionally, for the first time, we compared the metabolomic profile of these RCC patients pre-nephrectomy and 3 months and one year post-nephrectomy. We identified the dysregulated metabolomic variables by querying their exact mass against those presented in the Metlin and Human Metabolome Database. Next, we experimentally confirmed their identity. Both RCC subtypes showed similar metabolomic patterns at all stages. 51 metabolomic variables were significantly increased in RCC compared to controls and, among them, 4 were selected as potential discriminant metabolites between groups. We could experimentally confirm the identity of p-cresol glucuronide thus describing for the first time an increase in this metabolite in urine of RCC patients (fold change = 2.922, P = .012). Additionally, we confirmed that no metabolomic differences occur 3 months post-nephrectomy in RRC, while 188 variables were significantly increased one year post-nephrectomy. Of the 15 most discriminant metabolomic variables, we could experimentally confirm the identity of isobutyryl-l-carnitine (fold change = 2.098, P = .004) and l-proline betaine (fold change = 3.328, P = .004), for the first time. In summary, we have identified urine p-cresol glucuronide as potential diagnostic marker for RCC and isobutyryl-l-carnitine and l-proline betaine as potential prognostic markers. When confirmed in an independent cohort of RCC patients, these markers may improve the diagnosis and monitoring of RCC patients thus reducing current harmful diagnostic procedures. SIGNIFICANCE: The high-radiation dose of current imaging techniques available to diagnose and monitor renal cell carcinoma (RCC) are harmful for the patient and unspecific in low-grade tumors. Our untargeted metabolomic analysis carried out in urine samples from RCC patients and healthy individual reveals p-cresol glucuronide as potential diagnostic marker for RCC. Additionally, the analysis of RCC urine samples one year post-nephrectomy reveals isobutyryl-l-carnitine and l-proline betaine as potential prognostic markers. These novel non-invasive urine biomarkers may improve RCC management thus reducing the use of current harmful diagnostic techniques.

中文翻译：

透明细胞和乳头状肾细胞癌的尿代谢组学分析：一项初步研究。

肾细胞癌（RCC）是最致命的一种肿瘤，男性的发病率是女性的两倍。最初的症状不明确且过时，因此增加了死亡率。而且，当前的诊断和监测工具对患者有害并且对于低度肿瘤没有特异性。因此，需要新的微创标记物来诊断和监测RCC患者。尿液代表RCC的非侵入性生物标志物的理想样品来源。在我们的研究中，我们旨在确定具有诊断目的的RCC患者的尿代谢组学特征，并确定具有预后价值的特征。通过UPLC-Q-ToF MS非靶向代谢组学分析，我们比较了23例RCC患者（手术前14例透明细胞RCC和9例乳头状RCC）和23例健康对照者的代谢组学特征。另外，我们首次比较了这些RCC肾切除术前和肾切除术后3个月零一年的患者的代谢组学特征。我们通过查询与Metlin和人类代谢组学数据库中呈现的变量的确切质量，来识别代谢失调的变量。接下来，我们通过实验确认了其身份。两种RCC亚型在所有阶段均表现出相似的代谢组学模式。与对照组相比，RCC中51个代谢组学变量显着增加，其中4个被选为组间潜在的判别性代谢物。我们可以通过实验证实对甲酚葡萄糖醛酸的身份，从而首次描述了RCC患者尿液中这种代谢产物的增加（倍数变化= 2.922，P = .012）。另外，我们证实，肾切除术后3个月，RRC并未发生代谢组学差异，而肾切除术后一年，188个变量显着增加。在15个最有区别的代谢组学变量中，对于第一次。总之，我们已将尿中的对甲酚葡萄糖醛酸作为RCC的潜在诊断标记，将异丁酰-1-肉碱和L-脯氨酸甜菜碱作为潜在的预后标记。如果在独立的RCC患者队列中得到确认，这些标志物可以改善RCC患者的诊断和监测，从而减少当前有害的诊断程序。意义：当前可用于诊断和监测肾细胞癌（RCC）的成像技术的高辐射剂量对患者有害，对低度肿瘤无特异性。我们在来自RCC患者和健康个体的尿液样本中进行的非目标代谢组学分析显示，对甲酚葡萄糖醛酸苷可以作为RCC的潜在诊断标记。此外，肾切除术后一年对RCC尿液样本的分析显示，异丁酰-1-肉碱和1-脯氨酸甜菜碱是潜在的预后指标。这些新颖的非侵入性尿液生物标志物可以改善RCC管理，从而减少当前有害诊断技术的使用。我们在来自RCC患者和健康个体的尿液样本中进行的非目标代谢组学分析显示，对甲酚葡萄糖醛酸苷可以作为RCC的潜在诊断标记。此外，肾切除术后一年对RCC尿液样本的分析显示，异丁酰-1-肉碱和1-脯氨酸甜菜碱是潜在的预后指标。这些新颖的非侵入性尿液生物标志物可以改善RCC管理，从而减少当前有害诊断技术的使用。我们在来自RCC患者和健康个体的尿液样本中进行的非目标代谢组学分析显示，对甲酚葡萄糖醛酸苷可以作为RCC的潜在诊断标记。此外，肾切除术后一年对RCC尿液样本的分析显示，异丁酰-1-肉碱和1-脯氨酸甜菜碱是潜在的预后指标。这些新颖的非侵入性尿液生物标志物可以改善RCC管理，从而减少当前有害诊断技术的使用。

更新日期：2020-03-02

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