Objective: Although germline mutations of fumarate hydratase (FH) are a useful molecular marker of hereditary leiomyomatosis and renal cell cancer (RCC) syndrome, their clinical significance in sporadic RCC has not been studied in detail. The aim of the present study was to investigate possible correlations between the expression of FH and the clinical implications of sporadic RCC. Materials and Methods:FH mRNA levels were evaluated in 140 tumor specimens from patients with primary RCC and in 62 specimens of corresponding normal-appearing kidney tissue using real-time quantitative polymerase chain reaction. Immunohistochemical staining was performed on 6 normal surrounding tissues and 71 RCC tissues. Results:FH mRNA levels were significantly lower in tumor tissues than in matched normal-appearing kidney tissues (p = 0.031). In all normal tissues, FH staining intensity was strong. However, the expression of FH showed no significant correlation with the pathological and clinical characteristics of patients with sporadic RCC. Conclusions: Our results showed that FH mRNA expression decreased significantly in correlation with the transition from normal renal parenchyma to RCC. FH may be an indicator or tumorigenesis in sporadic RCC and could be a potential target for therapies against RCC in the future.

Keywords:
Fumarate hydratase, Renal cell cancer, mRNA, Tumorigenesis
1.
Sandim V, Pereira DA, Ornellas AA, Alves G: Renal cell carcinoma and proteomics. Urol Int 2010;84:373-377.
2.
Kwon WA, Park C, Kim EJ, Ha YS, Kim YJ, Yun SJ, Lee SC, Kim WJ: The relationship between RUNX3 inactivation and its pathological features in renal cell carcinoma. Korean J Urol 2009;50:432-438.
3.
Parkin DM, Bray F, Ferlay J, Pisani P: Global cancer statistics, 2002. CA Cancer J Clin 2005;55:74-108.
4.
Devesa SS, Silverman DT, McLaughlin JK, Brown CC, Connelly RR, Fraumeni JF, Jr: Comparison of the descriptive epidemiology of urinary tract cancers. Cancer Causes Control 1990;1:133-141.
5.
Thoenes W, Storkel S, Rumpelt HJ: Histopathology and classification of renal cell tumors (adenomas, oncocytomas and carcinomas). The basic cytological and histopathological elements and their use for diagnostics. Pathol Res Pract 1986;181:125-143.
6.
Rathmell WK, Wright TM, Rini BI: Molecularly targeted therapy in renal cell carcinoma. Expert Rev Anticancer Ther 2005;5:1031-1040.
7.
King A, Selak MA, Gottlieb E: Succinate dehydrogenase and fumarate hydratase: linking mitochondrial dysfunction and cancer. Oncogene 2006;25:4675-4682.
8.
Grubb RL 3rd, Franks ME, Toro J, Middelton L, Choyke L, Fowler S, Torres-Cabala C, Glenn GM, Choyke P, Merino MJ, Zbar B, Pinto PA, Srinivasan R, Coleman JA, Linehan WM: Hereditary leiomyomatosis and renal cell cancer: a syndrome associated with an aggressive form of inherited renal cancer. J Urol 2007;177:2074-2079; discussion 2079-2080.
9.
Pithukpakorn M, Wei MH, Toure O, Steinbach PJ, Glenn GM, Zbar B, Linehan WM, Toro JR: Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer. J Med Genet 2006;43:755-762.
10.
Pollard PJ, Briere JJ, Alam NA, Barwell J, Barclay E, Wortham NC, Hunt T, Mitchell M, Olpin S, Moat SJ, Hargreaves IP, Heales SJ, Chung YL, Griffiths JR, Dalgleish A, McGrath JA, Gleeson MJ, Hodgson SV, Poulsom R, Rustin P, Tomlinson IP: Accumulation of Krebs cycle intermediates and over-expression of HIF1α in tumours which result from germline FH and SDH mutations. Hum Mol Genet 2005;14:2231-2239.
11.
Isaacs JS, Jung YJ, Mole DR, Lee S, Torres-Cabala C, Chung YL, Merino M, Trepel J, Zbar B, Toro J, Ratcliffe PJ, Linehan WM, Neckers L: HIF overexpression correlates with biallelic loss of fumarate hydratase in renal cancer: novel role of fumarate in regulation of HIF stability. Cancer Cell 2005;8:143-153.
12.
Foster K, Prowse A, van den Berg A, et al: Somatic mutations of the von Hippel-Lindau disease tumour suppressor gene in non-familial clear cell renal carcinoma. Hum Mol Genet 1994;3:2169-2173.
13.
Gnarra JR, Tory K, Weng Y, et al: Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet 1994;7:85-90.
14.
Kiuru M, Lehtonen R, Arola J, Salovaara R, Jarvinen H, Aittomaki K, Sjoberg J, Visakorpi T, Knuutila S, Isola J, Delahunt B, Herva R, Launonen V, Karhu A, Aaltonen LA: Few FH mutations in sporadic counterparts of tumor types observed in hereditary leiomyomatosis and renal cell cancer families. Cancer Res 2002;62:4554-4557.
15.
Morris MR, Maina E, Morgan NV, Gentle D, Astuti D, Moch H, Kishida T, Yao M, Schraml P, Richards FM, Latif F, Maher ER: Molecular genetic analysis of FIH-1, FH, and SDHB candidate tumour suppressor genes in renal cell carcinoma. J Clin Pathol 2004;57:706-711.
16.
Greene FL: The American Joint Committee on Cancer: updating the strategies in cancer staging. Bull Am Coll Surg 2002;87:13-15.
17.
Fuhrman SA, Lasky LC, Limas C: Prognostic significance of morphologic parameters in renal cell carcinoma. Am J Surg Pathol 1982;6:655-663.
18.
Bland JM, Altman DG: Transformations, means, and confidence intervals. BMJ 1996;312:1079.
19.
Lipworth L, Tarone RE, McLaughlin JK: The epidemiology of renal cell carcinoma. J Urol 2006;176:2353-2358.
20.
Coleman JA: Familial and hereditary renal cancer syndromes. Urol Clin North Am 2008;35:563-572, v.
21.
Cohen D, Zhou M: Molecular genetics of familial renal cell carcinoma syndromes. Clin Lab Med 2005;25:259-277.
22.
Pfaffenroth EC, Linehan WM: Genetic basis for kidney cancer: opportunity for disease-specific approaches to therapy. Expert Opin Biol Ther 2008;8:779-790.
23.
Eng C, Kiuru M, Fernandez MJ, Aaltonen LA: A role for mitochondrial enzymes in inherited neoplasia and beyond. Nat Rev Cancer 2003;3:193-202.
24.
Shulman RG, Rothman DL, Behar KL, Hyder F: Energetic basis of brain activity: implications for neuroimaging. Trends Neurosci 2004;27:489-495.
25.
Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G: Overexpression of hypoxia-inducible factor-1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 2000;60:4693-4696.
26.
Talks KL, Turley H, Gatter KC, Maxwell PH, Pugh CW, Ratcliffe PJ, Harris AL: The expression and distribution of the hypoxia-inducible factors HIF-1α and HIF-2α in normal human tissues, cancers, and tumor-associated macrophages. Am J Pathol 2000;157:411-421.
27.
Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, Buechler P, Isaacs WB, Semenza GL, Simons JW: Overexpression of hypoxia-inducible factor-1α in common human cancers and their metastases. Cancer Res 1999;59:5830-5835.
28.
Ashrafian H, O'Flaherty L, Adam J, Steeples V, Chung YL, East P, Vanharanta S, Lehtonen H, Nye E, Hatipoglu E, Miranda M, Howarth K, Shukla D, Troy H, Griffiths J, Spencer-Dene B, Yusuf M, Volpi E, Maxwell PH, Stamp G, Poulsom R, Pugh CW, Costa B, Bardella C, Di Renzo MF, Kotlikoff MI, Launonen V, Aaltonen L, El-Bahrawy M, Tomlinson I, Pollard PJ: Expression profiling in progressive stages of fumarate-hydratase deficiency: the contribution of metabolic changes to tumorigenesis. Cancer Res 2010;70:9153-9165.
29.
Rini BI, Rathmell WK: Biological aspects and binding strategies of vascular endothelial growth factor in renal cell carcinoma. Clin Cancer Res 2007;13:741s-746s.
30.
Rini BI: Metastatic renal cell carcinoma: many treatment options, one patient. J Clin Oncol 2009;27:3225-3234.
© 2012 S. Karger AG, Basel
2012
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.