Genotype and tumor locus determine expression profile of pseudohypoxic pheochromocytomas and paragangliomas

Uma Shankavaram, Stephanie M.J. Fliedner, Abdel G. Elkahloun, Jenifer J. Barb, Peter J. Munson, Thanh T. Huynh, Joey C. Matro, Hana Turkova, W. Marston Linehan, Henri J. Timmers, Arthur S. Tischler, James F. Powers, Ronald de Krijger, Bora E. Baysal, Martina Takacova, Silvia Pastorekova, David Gius, Hendrik Lehnert, Kevin Camphausen, Karel Pacak*

*Corresponding author for this work

Research output: Contribution to journalArticle

23 Scopus citations

Abstract

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) related to mutations in the mitochondrial succinate dehydrogenase (SDH) subunits A, B, C, and D, SDH complex assembly factor 2, and the von Hippel-Lindau (VHL) genes share a pseudohypoxic expression profile. However, genotype-specific differences in expression have been emerging. Development of effective new therapies for distinctive manifestations, e.g., a high rate of malignancy in SDHB- or predisposition to multifocal PGLs in SDHD patients, mandates improved stratification. To identify mutation/location-related characteristics among pseudohypoxic PHEOs/PGLs, we used comprehensive microarray profiling (SDHB: n = 18, SDHD-abdominal/thoracic (AT): n = 6, SDHD-head/neck (HN): n = 8, VHL: n = 13). To avoid location-specific bias, typical adrenal medulla genes were derived from matched normal medullas and cortices (n = 8) for data normalization. Unsupervised analysis identified two dominant clusters, separating SDHB and SDHD-AT PHEOs/PGLs (cluster A) from VHL PHEOs and SDHD-HN PGLs (cluster B). Supervised analysis yielded 6937 highly predictive genes (misclassification error rate of 0.175). Enrichment analysis revealed that energy metabolism and inflammation/fibrosis-related genes were most pronouncedly changed in clusters A and B, respectively. A minimum subset of 40 classifiers was validated by quantitative real-time polymerase chain reaction (quantitative real-time polymerase chain reaction vs. microarray: r= 0.87). Expression of several individual classifiers was identified as characteristic for VHL and SDHD-HN PHEOs and PGLs. In the present study, we show for the first time that SDHD-HN PGLs share more features with VHL PHEOs than with SDHD-AT PGLs. The presented data suggest novel subclassification of pseudohypoxic PHEOs/PGLs and implies cluster-specific pathogenic mechanisms and treatment strategies.

Original languageEnglish (US)
Pages (from-to)435-447
Number of pages13
JournalNeoplasia (United States)
Volume15
Issue number4
DOIs
StatePublished - Apr 2013

ASJC Scopus subject areas

  • Cancer Research

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    Shankavaram, U., Fliedner, S. M. J., Elkahloun, A. G., Barb, J. J., Munson, P. J., Huynh, T. T., Matro, J. C., Turkova, H., Marston Linehan, W., Timmers, H. J., Tischler, A. S., Powers, J. F., de Krijger, R., Baysal, B. E., Takacova, M., Pastorekova, S., Gius, D., Lehnert, H., Camphausen, K., & Pacak, K. (2013). Genotype and tumor locus determine expression profile of pseudohypoxic pheochromocytomas and paragangliomas. Neoplasia (United States), 15(4), 435-447. https://doi.org/10.1593/neo.122132