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  • Oncogenomics
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Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma

Oncogene volume 26, pages 5680–5691 (2007)Cite this article

Abstract

Oncogenic wingless-related mouse mammary tumour virus (Wnt) signalling, caused by epigenetic inactivation of specific pathway regulators like the putative tumour suppressor secreted frizzled-related protein 1 (SFRP1), may be causally involved in the carcinogenesis of many human solid tumours including breast, colon and kidney cancer. To evaluate the incidence of SFRP1 deficiency in human tumours, we performed a large-scale SFRP1 expression analysis using immunohistochemistry on a comprehensive tissue microarray (TMA) comprising 3448 tumours from 36 organs. This TMA contained 132 different tumour subtypes as well as 26 different normal tissues. Although tumour precursor stages of, for example kidney, colon, endometrium or adrenal gland still exhibited moderate to abundant SFRP1 expression, this expression was frequently lost in the corresponding genuine tumours. We defined nine novel tumour entities with apparent loss of SFRP1 expression, i.e., cancers of the kidney, stomach, small intestine, pancreas, parathyroid, adrenal gland, gall bladder, endometrium and testis. Renal cell carcinoma (RCC) exhibited the highest frequency of SFRP1 loss (89% on mRNA level; 75% on protein level) and was selected for further analysis to investigate the cause of SFRP1 loss in human tumours. We performed expression, mutation and methylation analysis in RCC and their matching normal kidney tissues. SFRP1 promoter methylation was frequently found in RCC (68%, n=38) and was correlated with loss of SFRP1 mRNA expression (p<0.05). Although loss of heterozygosity was found in 16% of RCC, structural mutations in the coding or promoter region of the SFRP1 gene were not observed. Our results indicate that loss of SFRP1 expression is a very common event in human cancer, arguing for a fundamental role of aberrant Wnt signalling in the development of solid tumours. In RCC, promoter hypermethylation seems to be the predominant mechanism of SFRP1 gene silencing and may contribute to initiation and progression of this disease.

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Acknowledgements

The expert technical assistance of Sonja von Serényi (Institute of Pathology, RWTH Aachen), Rudolf Jung (Institute of Pathology, University Regensburg), Kerstin Reher and Nina Niessl (Department of Urology, University Regensburg) is greatly appreciated. The study was supported by the German Ministry for Education and Research (BMBF grant 01KW0404 to Edgar Dahl) as part of the German Human Genome Project (DHGP), by a grant from the RWTH Aachen (START program) to Edgar Dahl and by the University of Regensburg to Christine Hammerschmied (Regensburger Forschungsfoerderung in der Medizin: ReForM A).

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  1. E Dahl and F Wiesmann: These two authors contributed equally to this work.

Authors and Affiliations

  1. Molecular Oncology Group, Institute of Pathology, University Hospital of the RWTH Aachen, Aachen, Germany

    E Dahl, F Wiesmann, J Veeck & R Knüchel

  2. Institute of Pathology, University of Regensburg, Regensburg, Germany

    M Woenckhaus & A Hartmann

  3. Department of Urology, University of Regensburg, Regensburg, Germany

    R Stoehr, W F Wieland, B Walter, S Denzinger & C G Hammerschmied

  4. Institute of Pathology, University of Zürich, Zürich, Switzerland

    P J Wild

  5. Institute for Medical Genetics, Charité, Universitätsmedizin Berlin, Berlin, Germany

    E Klopocki

  6. Institute of Pathology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

    G Sauter & R Simon

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Correspondence to E Dahl.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Dahl, E., Wiesmann, F., Woenckhaus, M. et al. Frequent loss of SFRP1 expression in multiple human solid tumours: association with aberrant promoter methylation in renal cell carcinoma. Oncogene 26, 5680–5691 (2007). https://doi.org/10.1038/sj.onc.1210345

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