title: Genotype and tumor locus determine expression profile of pseudohypoxic pheochromocytomas and paragangliomas.
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.
authors.affiliation: Radiation Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-1109, USA.
authors.forename: Uma
authors.initials: U
authors.lastname: Shankavaram
authors.forename: Stephanie M J
authors.initials: SM
authors.lastname: Fliedner
authors.forename: Abdel G
authors.initials: AG
authors.lastname: Elkahloun
authors.forename: Jenifer J
authors.initials: JJ
authors.lastname: Barb
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Munson
authors.forename: Thanh T
authors.initials: TT
authors.lastname: Huynh
authors.forename: Joey C
authors.initials: JC
authors.lastname: Matro
authors.forename: Hana
authors.initials: H
authors.lastname: Turkova
authors.forename: W Marston
authors.initials: WM
authors.lastname: Linehan
authors.forename: Henri J
authors.initials: HJ
authors.lastname: Timmers
authors.forename: Arthur S
authors.initials: AS
authors.lastname: Tischler
authors.forename: James F
authors.initials: JF
authors.lastname: Powers
authors.forename: Ronald
authors.initials: R
authors.lastname: de Krijger
authors.forename: Bora E
authors.initials: BE
authors.lastname: Baysal
authors.forename: Martina
authors.initials: M
authors.lastname: Takacova
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastorekova
authors.forename: David
authors.initials: D
authors.lastname: Gius
authors.forename: Hendrik
authors.initials: H
authors.lastname: Lehnert
authors.forename: Kevin
authors.initials: K
authors.lastname: Camphausen
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000368:Aged; D015687:Cell Hypoxia; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D005260:Female; D005838:Genotype; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010085:Oxidative Phosphorylation; D010235:Paraganglioma / Q000235:genetics / Q000378:metabolism; D010673:Pheochromocytoma / Q000235:genetics* / Q000378:metabolism; D025341:Principal Component Analysis; D013385:Succinate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: C491545:SDHD protein, human; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human
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