Downregulation of metastasis suppressor genes in malignant pheochromocytoma

Shoichiro Ohta, Edwin W. Lai, Alan L.Y. Pang, Frederieke M. Brouwers, Wai Yee Chan, Graeme Eisenhofer, Ronald De Krijger, Lucia Ksinantova, Jan Breza, Pavel Blazicek, Richard Kvetnansky, Robert A. Wesley, Karel Pacak*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

85 Citations (Scopus)


There is no reliable method currently available to predict malignant potential of pheochromocytoma based on conventional histology or genetic, molecular or immunohistochemical markers. Metastasis suppressor genes affect the spread of several cancers and, therefore, may provide promise as prognostic markers or therapeutic targets for malignant pheochromocytoma. We hypothesized that the downregulation of metastasis suppressor genes in malignant pheochromocytoma may play a role in malignant behavior. We applied quantitative real-time polymerase chain reaction (QRT-PCR) to 11 metastasis suppressor genes. These genes are known to be involved in the regulation of important cancer-related cellular events, such as cell growth regulation and apoptosis (nm23-H1, TIMP-1, TIMP-2, TIMP-3, TIMP-4, TXNIP and CRSP-3), cell-cell communication (BRMS-1), invasion (CRMP-1) and cell adhesion (E-Cad and KiSS1). The study included 15 benign and 10 malignant pheochromocytomas. Six metastasis suppressor genes (nm23-H1, TIMP-4, BRMS-1, TXNIP, CRSP-3 and E-Cad) were downregulated significantly in malignant compared to benign pheochromocytoma (p < 0.05, Mann-Whitney U-test). We applied a non-linear rule using median malignant value (MMV) as a threshold to use metastasis suppressor genes to distinguish malignant from benign samples. After cross-validation, the non-linear rule produced no errors in 10 malignant samples and 3 errors in the 15 benign samples, with an overall error rate of 12%. These results suggest that downregulation of metastasis suppressor genes reflect malignant pheochromocytoma with a high degree of sensitivity. Thus, we conclude that altered function of these metastasis suppressor gene pathways may play an important role in the malignant behavior of pheochromocytoma.

Original languageEnglish
Pages (from-to)139-143
Number of pages5
JournalInternational Journal of Cancer
Issue number1
Publication statusPublished - 10 Mar 2005


  • Metastasis
  • Pheochromocytoma
  • Real-time PCR


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