Aberrant succination of proteins in fumarate hydratase-deficient mice and HLRCC patients is a robust biomarker of mutation status

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....

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Vydáno v:	The Journal of pathology Ročník 225; číslo 1; s. 4 - 11
Hlavní autoři:	Bardella, Chiara, El-Bahrawy, Mona, Frizzell, Norma, Adam, Julie, Ternette, Nicola, Hatipoglu, Emine, Howarth, Kimberley, O'Flaherty, Linda, Roberts, Ian, Turner, Gareth, Taylor, Jennifer, Giaslakiotis, Konstantinos, Macaulay, Valentine M, Harris, Adrian L, Chandra, Ashish, Lehtonen, Heli J, Launonen, Virpi, Aaltonen, Lauri A, Pugh, Christopher W, Mihai, Radu, Trudgian, David, Kessler, Benedikt, Baynes, John W, Ratcliffe, Peter J, Tomlinson, Ian P, Pollard, Patrick J
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Chichester, UK John Wiley & Sons, Ltd 01.09.2011 Wiley
Témata:	Adult Aged Animal models Animals Antibodies Biological and medical sciences biomarkers Biomarkers, Tumor - deficiency Biomarkers, Tumor - genetics Biomarkers, Tumor - metabolism Cancer Carcinoma, Renal Cell - diagnosis Carcinoma, Renal Cell - genetics Cysteine Cysts Disease Models, Animal Enzymes Female Fumarate hydratase Fumarate Hydratase - deficiency Fumarate Hydratase - genetics Fumarate Hydratase - metabolism Genetic analysis Genetic Predisposition to Disease Genetic screening Germ-Line Mutation HLRCC Humans immunhistochemistry Immunohistochemistry Investigative techniques, diagnostic techniques (general aspects) Kidney Kidney Neoplasms - diagnosis Kidney Neoplasms - genetics Kidneys Leiomyomatosis - diagnosis Leiomyomatosis - genetics Loss of Heterozygosity Male Medical sciences Metabolites Mice Mice, Knockout Mice, Transgenic Middle Aged mitochondria mouse models Mutation Neoplastic Syndromes, Hereditary - diagnosis Neoplastic Syndromes, Hereditary - genetics Nephrology. Urinary tract diseases Pathology. Cytology. Biochemistry. Spectrometry. Miscellaneous investigative techniques Prospective Studies renal cancer Sensitivity and Specificity succination Succinic Acid - metabolism Tricarboxylic acid cycle Tumorigenesis Tumors of the urinary system mouse models Animal model Biological marker renal cancer Lyases Mitochondria Genetics Anomaly Kidney disease Human Urinary system disease Enzyme Deficiency succination Rodentia Biological indicator Malignant tumor Protein Fumarate hydratase Vertebrata Anatomic pathology Mammalia Mouse HLRCC Animal Kidney cancer Mutation Carbon-oxygen lyases immunhistochemistry Cancer Hydro-lyases
ISSN:	0022-3417, 1096-9896, 1096-9896
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Shrnutí:	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 © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Bibliografie:	Supporting Information: Figure S1. 2SCP expression results from loss of Fh1 protein in mouse embryonic fibroblasts.Supporting Information: Figure S2. Succination of murine Gapdh in FH-deficient kidneys.Supporting Information: Table S1. 2SCP immunohistochemistry and FH mutation status of PRCCs derived from Oxford Radcliffe Hospitals.Supporting Information: Table S2. Details of the biopsies screened for 2SCP by immunohistochemistry.Supporting Information: Supplementary methods: PCR conditions and primer sequences for FH mutation screening. Conflict of interest statement. PP, NF, JWB and IPT have filed for a patent [No. USC-268-P(849)] covering immunohistochemical screening for the determination of FH mutations. istex:D0E64E8A3A5B4FAC20392F9C716D32E20CC9C750 ark:/67375/WNG-JVKL5SCN-Z ArticleID:PATH2932 Conflict of interest statement. PP, NF, JWB and IPT have filed for a patent [No. USC‐268‐P(849)] covering immunohistochemical screening for the determination of FH mutations. These authors contributed equally to this work. ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0022-3417 1096-9896 1096-9896
DOI:	10.1002/path.2932