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

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ID: 212903
2013
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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.
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shankavaram2013neoplasia:genotype Use this key to autocite in the manuscript while using SciMatic Manuscript Manager or Thesis Manager
Authors ;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
Journal ACS chemical neuroscience
Year 2013
DOI
10.1593/neo.122132
URL
http://www.sciencedirect.com/science/article/pii/S1476558613800504
Keywords
neoplasms Oncology including cancer and carcinogens tumors

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