Genotype and Tumor Location Determine Expression Profiles of Pseudohypoxic Pheochromocytomas and Paragangliomas

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 17-28-Adrenal Tumors & Pheochromocytoma
Basic/Clinical
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-20
Stephanie M J Fliedner*1, Uma Shankavaram2, Abdel G Elkahloun3, Thanh Huynh4, Hana Turkova4, Joey C Matro4, Jenifer J Barb5, Peter J Munson5, W Marston Linehan6, Henri JLM Timmers7, Arthur S Tischler8, James F Powers8, Ronald de Krijger9, Bora E Baysal10, Martina Takacova11, Silvia Pastorekova11, David Gius12, Hendrik Lehnert1, Kevin Camphausen2 and Karel Pacak13
1University Hospital Schleswig-Holstein, Lübeck, Lübeck, Germany, 2National Cancer Institute, National Institutes of Health, Bethesda, MD, 3National Human Genome Research Institute, National Institutes of Health, Bethesda, 4Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, 5Center for Information Technology, National Institutes of Health, Bethesda, MD, 6National Cancer Institute, National Institutes of Health, 7Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, 8Tufts Medical Center, Boston, MA, 9Josephine Nefkens Institute, Erasmus MC-University Medical Center, Rotterdam, 10Rosewell Park Cancer Institute, Buffalo, NY, 11Slovak Academy of Sciences, Bratislava, Slovakia, 12Feinberg Northwestern Medical School, Chicago, IL, 13National Institutes of Health (NIH), Bethesda, MD
Pheochromocytomas (PHEOs) and paragangliomas (PGLs) related to mutations in the mitochondrial succinate dehydrogenase (SDH) subunit A, B, C, 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 clinical features, e.g. a high rate of malignancy in SDHB patients or predisposition to multifocal PGLs in SDHD patients mandates new stratification tools. To identify mutation/location-related characteristics among pseudohypoxic PHEOs/PGLs we used comprehensive microarray gene expression profiling (SDHB: n=18, SDHD-abdominal/thoracic (AT): n=6, SDHD-head/neck (HN): n=8, VHL: n=13). To avoid location-specific expression bias, typical adrenal medulla genes were derived from matched normal medullae 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 6,937 highly predictive genes (misclassification error rate 0.175). Enrichment analysis revealed that energy metabolism and inflammation/fibrosis related genes were most pronouncedly changed in cluster-A and -B, respectively. A minimum subset of 40 classifiers was validated by quantitative RT-PCR (qRT-PCR vs. microarray: r = 0.87). Expression of several individual classifiers was identified as characteristic for VHL and SDHD-HN PHEOs and PGLs, respectively.

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 suggests novel sub-classification of pseudohypoxic PHEOs/PGLs and implies cluster specific pathogenic mechanisms and treatment strategies accordingly.

SF and US contributed equally to this work.

Nothing to Disclose: SMJF, US, AGE, TH, HT, JCM, JJB, PJM, WML, HJT, AST, JFP, RD, BEB, MT, SP, DG, HL, KC, KP

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD