TY - JOUR
T1 - Genotype and tumor locus determine expression profile of pseudohypoxic pheochromocytomas and paragangliomas
AU - Shankavaram, Uma
AU - Fliedner, Stephanie M.J.
AU - Elkahloun, Abdel G.
AU - Barb, Jenifer J.
AU - Munson, Peter J.
AU - Huynh, Thanh T.
AU - Matro, Joey C.
AU - Turkova, Hana
AU - Marston Linehan, W.
AU - Timmers, Henri J.
AU - Tischler, Arthur S.
AU - Powers, James F.
AU - de Krijger, Ronald
AU - Baysal, Bora E.
AU - Takacova, Martina
AU - Pastorekova, Silvia
AU - Gius, David
AU - Lehnert, Hendrik
AU - Camphausen, Kevin
AU - Pacak, Karel
N1 - Funding Information:
Abbreviations: AT, abdominal/thoracic; CSS, Carney-Stratakis Syndrome; HIF2α, hypoxia-inducible factor 2α; HN, head/neck; IPA, Ingenuity Pathway Analysis; NF1/NF1, neurofibromatosis 1 syndrome/gene; OXPHOS, oxidative phosphorylation; PAMR, prediction analysis for microarray; PGL, paraganglioma; PGL1, 2, 3, 4, familial PGL types 1, 2, 3, 4; PHD, prolyl hydroxylase; PHD2/EGLN1, prolyl hydroxylase 2; PHEO, pheochromocytoma; qRT-PCR, quantitative real-time polymerase chain reaction; SAM, significance analysis of microarray; SDH, succinate dehydrogenase; SDHA, SDH subunit A; SDHAF2, SDH complex assembly factor 2; SDHB, SDH subunit B; SDHC, SDH subunit C; SDHD, SDH subunit D; TMEM127, transmembrane protein 127; VHL/VHL, von Hippel-Lindau syndrome/gene Address all correspondence to: Karel Pacak, MD, PhD, DSc, Chief, Section on Medical Neuroendocrinology, Professor of Medicine, Program in Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Building 10, CRC, 1-East, Room 1-3140, 10 Center Drive, Bethesda, MD 20892-1109. E-mail: [email protected] 1This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and the National Human Genome Research Institute, National Institutes of Health (Bethesda, MD). The authors have nothing to disclose. 2This article refers to supplementary materials, which are designated by Tables W1 to W3 and Figures W1 to W3 and are available online at www.neoplasia.com. 3These authors contributed equally. Received 17 December 2012; Revised 1 February 2013; Accepted 4 February 2013 Copyright © 2013 Neoplasia Press, Inc. All rights reserved 1522-8002/13/$25.00 DOI 10.1593/neo.122132
PY - 2013/4
Y1 - 2013/4
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84875640167&partnerID=8YFLogxK
U2 - 10.1593/neo.122132
DO - 10.1593/neo.122132
M3 - Article
AN - SCOPUS:84875640167
SN - 1522-8002
VL - 15
SP - 435
EP - 447
JO - Neoplasia (United States)
JF - Neoplasia (United States)
IS - 4
ER -