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DOI: 10.1055/s-0033-1336697
Genotype and tumor location determine gene expression signatures in pseudohypoxic pheochromocytomas and paragangliomas
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