Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status
Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status
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DOI：
10.1002/path.2932
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发表时间：
2011-09-01
影响因子：
7.3
通讯作者：
Pollard, Patrick J.
中科院分区：
文献类型：
--
作者：
Bardella, Chiara;El-Bahrawy, Mona;Pollard, Patrick J.
编码克雷布斯循环酶富马酸水合酶的FH基因的种系突变易患遗传性平滑肌瘤病和肾细胞癌（HLRCC）综合征。FH缺陷细胞和组织积累高水平的富马酸盐，其可能作为癌代谢产物并促进肿瘤发生。最近提出的富马酸在半胱氨酸残基共价修饰为S-（2-琥珀酰）半胱氨酸（2SC）（称为蛋白琥珀酰化）中的作用促使我们评估现有HLRCC模型中的2SC水平。在此，使用先前表征的针对2SC的抗体，我们表明FH的基因消融导致高水平的蛋白琥珀酸化。我们接下来假设2SC的免疫组织化学将作为FH缺陷组织原位检测的代谢生物标志物。在Fh 1（鼠FH）缺陷性肾囊肿和具有确定FH突变的HLRCC肿瘤（n = 16）的回顾性系列中观察到2SC的稳健检测。重要的是，在正常组织（n = 200）和与HLRCC无关的肿瘤类型（n = 1342）中检测不到2SC。在对转介进行HLRCC基因检测的病例进行的前瞻性评估中，2SC修饰蛋白（2SCP）的存在正确地预测了每个病例中FH的遗传变异。在两个系列的II型乳头状肾癌（PRCC）中，通过2SCP染色和遗传分析进行前瞻性分析，生物标志物准确地识别了先前未怀疑的FH突变（2/33和1/36）。研究其他肿瘤类型中的代谢物是否产生可以使用类似策略测定的蛋白质修饰特征，将在未来的癌症研究中引起兴趣。版权所有（C）2011大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
Germline mutations in the FH gene encoding the Krebs cycle enzyme fumarate hydratase predispose to hereditary leiomyomatosis and renal cell cancer (HLRCC) syndrome. FH-deficient cells and tissues accumulate high levels of fumarate, which may act as an oncometabolite and contribute to tumourigenesis. A recently proposed role for fumarate in the covalent modification of cysteine residues to S-(2-succinyl) cysteine (2SC) (termed protein succination) prompted us to assess 2SC levels in our existing models of HLRCC. Herein, using a previously characterized antibody against 2SC, we show that genetic ablation of FH causes high levels of protein succination. We next hypothesized that immunohistochemistry for 2SC would serve as a metabolic biomarker for the in situ detection of FH-deficient tissues. Robust detection of 2SC was observed in Fh1 (murine FH)-deficient renal cysts and in a retrospective series of HLRCC tumours (n = 16) with established FH mutations. Importantly, 2SC was undetectable in normal tissues (n = 200) and tumour types not associated with HLRCC (n = 1342). In a prospective evaluation of cases referred for genetic testing for HLRCC, the presence of 2SC-modified proteins (2SCP) correctly predicted genetic alterations in FH in every case. In two series of unselected type II papillary renal cancer (PRCC), prospectively analysed by 2SCP staining followed by genetic analysis, the biomarker accurately identified previously unsuspected FH mutations (2/33 and 1/36). The investigation of whether metabolites in other tumour types produce protein modification signature(s) that can be assayed using similar strategies will be of interest in future studies of cancer. Copyright (C) 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.