Targeted Quantification of Carbon Metabolites Identifies Metabolic Progression Markers and an Undiagnosed Case of SDH-Deficient Clear Cell Renal Cell Carcinoma in a German Cohort.
Targeted Quantification of Carbon Metabolites Identifies Metabolic Progression Markers and an Undiagnosed Case of SDH-Deficient Clear Cell Renal Cell Carcinoma in a German Cohort.
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DOI：
10.3390/metabo11110764
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发表时间：
2021-11-09
期刊：
影响因子：
4.1
通讯作者：
Richter S
中科院分区：
文献类型：
--
作者：
William D;Erdmann K;Ottemöller J;Mangelis A;Conrad C;Peitzsch M;Schröck E;Eisenhofer G;Zacharis A;Füssel S;Aust D;Klink B;Richter S
肾细胞癌(RCC)是10种最常见的癌症实体之一，根据Krebs周期基因的差异表达可分为不同的亚型。我们在420例未选择的RCC队列中调查了几种靶向代谢物对肿瘤分期和患者生存的预测价值。代谢物比率的非监督等级聚类确定了由α-酮戊二酸(α-KG)水平分隔的两个主要簇和具有不同水平的肿瘤代谢物2-羟基戊二酸(2HG)的亚簇。以高2HG为特征的亚群在较高的肿瘤分期中丰富，提示代谢物特征可能是肿瘤分期或生存的合适预测因子。基于单一代谢物特征的Bootstrap森林模型显示，乳酸、2HG、柠檬酸、天冬氨酸、天冬酰胺和谷氨酰胺更好地预测透明细胞肾癌患者的癌症特异性生存，而琥珀酸和α-酮戊二酸则更好地预测乳头状肾癌患者的癌症特异性生存。此外，这项检测还发现了罕见的具有SDHx突变的肿瘤病例，这些突变主要是由种系突变引起的，容易发生不同的肿瘤。因此，应进一步评估选定代谢物的分析在液体活组织检查中的潜在用途，液体活组织检查可以使用侵入性较小的方法获得，并有可能促进患者和照顾者的疾病监测。
Renal cell carcinoma (RCC) is among the 10 most common cancer entities and can be categorised into distinct subtypes by differential expression of Krebs cycle genes. We investigated the predictive value of several targeted metabolites with regards to tumour stages and patient survival in an unselected cohort of 420 RCCs. Unsupervised hierarchical clustering of metabolite ratios identified two main clusters separated by α-ketoglutarate (α-KG) levels and sub-clusters with differential levels of the oncometabolite 2-hydroxyglutarate (2HG). Sub-clusters characterised by high 2HG were enriched in higher tumour stages, suggesting metabolite profiles might be suitable predictors of tumour stage or survival. Bootstrap forest models based on single metabolite signatures showed that lactate, 2HG, citrate, aspartate, asparagine, and glutamine better predicted the cancer-specific survival (CSS) of clear cell RCC patients, whereas succinate and α-ketoglutarate were better CSS predictors for papillary RCC patients. Additionally, this assay identifies rare cases of tumours with SDHx mutations, which are caused predominantly by germline mutations and which predispose to development of different neoplasms. Hence, analysis of selected metabolites should be further evaluated for potential utility in liquid biopsies, which can be obtained using less invasive methods and potentially facilitate disease monitoring for both patients and caregivers.
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影响因子：
4.7
作者：
Briston T;Stephen JM;Thomas LW;Esposito C;Chung YL;Syafruddin SE;Turmaine M;Maddalena LA;Greef B;Szabadkai G;Maxwell PH;Vanharanta S;Ashcroft M
通讯作者：
Ashcroft M
影响因子：
--
作者：
Lucarelli G;Galleggiante V;Rutigliano M;Sanguedolce F;Cagiano S;Bufo P;Lastilla G;Maiorano E;Ribatti D;Giglio A;Serino G;Vavallo A;Bettocchi C;Selvaggi FP;Battaglia M;Ditonno P
通讯作者：
Ditonno P
影响因子：
5.6
作者：
Williamson, Sean R.;Gill, Anthony J.;Hes, Ondrej
通讯作者：
Hes, Ondrej
影响因子：
5.2
作者：
Gieldon, Laura;William, Doreen;Klink, Barbara
通讯作者：
Klink, Barbara
影响因子：
4.4
作者：
Lin, Lin;Huang, Zhenzhen;Hang, Wei
通讯作者：
Hang, Wei