Exp Clin Endocrinol Diabetes 2013; 121 - P27
DOI: 10.1055/s-0033-1336697

Genotype and tumor location determine gene expression signatures in pseudohypoxic pheochromocytomas and paragangliomas

SM Fliedner 1, 2, U Shankavaram 3, AG Elkahloun 4, TT Huynh 2, WM Linehan 5, HJ Timmers 6, AS Tischler 7, J Powers 7, R de Krijger 8, B Baysal 9, G David 3, 10, H Lehnert 1, K Camphausen 3, K Pacak 2
  • 1University Hospital Schleswig-Holstein, 1st Department of Medicine, Lübeck, Germany
  • 2Eunice Kennedy Shriver National Institutes of Child Health and Human Development, Program of Reproductive and Adult Endocrinology, Bethesda, United States
  • 3National Cancer Institute, National Institutes of Health, Radiation Oncology Branch, Bethesda, United States
  • 4National Human Genome Research Institute, National Institutes of Health, Cancer Genetics Branch, Bethesda, United States
  • 5National Cancer Institute, National Institutes of Health, Urologic Oncology Branch, Center for Cancer Research, Bethesda, United States
  • 6Radboud University Nijmegen Medical Center, Department of Endocrinology, Nijmegen, Netherlands
  • 7Tufts Medical Center, Department of Pathology, Boston, United States
  • 8Josephine Nefkens Institute, Erasmus MC-University Medical Center, Department of Pathology, Rotterdam, Netherlands
  • 9Roswell Park Cancer Institute, Department of Pathology, Buffalo, United States
  • 10Feinberg Northwestern Medical School, Department of Radiation Oncology, Chicago, United States

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) related to mutations in the mitochondrial succinate dehydrogenase (SDH) subunit A, B, C, D, SDHAF2, 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.

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

*first and second author contributed equally