Pheochromocytoma/Paraganglioma: A Poster Child for Cancer Metabolism

Sergei G. Tevosian; Hans K. Ghayee


J Clin Endocrinol Metab. 2018;103(5):1779-1789. 

In This Article

Gene Clusters in PCC/PGLs

We now know that there are 21 genes associated with PCC/PGLs—more than any number of genes associated with any other endocrine tumor[12] (Table 1). A few years before the discovery of mutations in the SDHx complex, genes associated with PCC syndromes were isolated, such as neurofibromatosis type 1 and rearranged during transfection (RET) proto-oncogene, which is associated with multiple endocrine neoplasia 2 syndrome. How these different genes cause PCC/PGLs has been an area of intense investigation.

Depending on the type of the mutation, PCC/PGLs have distinctive gene expression profiles that assemble (cluster) in two so-called cluster groups.[37,38] Mutations affecting Von Hippel Lindau (VHL) protein and subunits of the succinate dehydrogenase (SDH) complex or SDH accessory proteins (i.e., SDHA, SDHB, SDHC, SDHD, and SDHAF2) and, rarely, isocitrate dehydrogenase (IDH) mutations, are among the causes of PCC/PGLs that make up cluster 1 tumors that are noradrenergic.[37,38] Most of the tumors that comprise cluster 1 are PGLs.[37,38] Their noradrenergic nature likely stems from the hypermethylation of the phenylethanolamine N-methyltransferase (PNMT) gene and subsequent lack of norepinephrine to epinephrine conversion. The proposed molecular mechanism involves inhibition of 2-oxoglutarate–dependent histone demethylases.[39] Neurofibromatosis type 1, transmembrane protein 127 and multiple endocrine neoplasma type 2 due to mutations of the RET gene are well-established causes of hereditary PCC/PGLs; these tumors constitute cluster 2.[40,41] Interestingly, DNA from the four living relatives of the first PCC/PGL patient described in 1886 demonstrated the presence of a germ-line RET mutation.[1]

Recently, The Cancer Genome Atlas Program verified the genetic composition of cluster 1 and cluster 2 tumors.[15] Most gene mutations giving rise to the noradrenergic cluster 1 phenotype are primarily associated with Krebs cycle enzyme mutations as well as the pseudohypoxia pathway. In contrast, mutations in cluster 2 genes are found in tumors with adrenergic phenotype. This comprehensive project also uncovered two additional gene expression clusters.[15] The third cluster is associated with an expression of the Mastermind-like 3 (MAML3)–fusion genes and the fourth is a cortical admixture phenotype.[15] The tumors containing MAML3 C-terminal fusions were associated with a distinctive expression profile, active Wnt signaling pathway, low level of DNA methylation, and adverse clinical outcomes. The cortical admixture subtype is distinguished by the overexpression of several adrenal cortex markers. In addition, cortical admixture subtype contains germline mutations in MAX, supporting a distinctive underlying biology.[15] Tumors with mutations in MYC-associated factor X (MAX) that regulates the MYC transcription factor are customarily assigned to cluster 2. However, MAX-associated tumors have a tendency for preferential secretion of normetanephrine compared with metanephrine.[42,43] Also, investigators have noted that the expression level of PNMT enzyme that converts norepinephrine to epinephrine is intermediate between tumors with the adrenergic phenotype and those with the noradrenergic phenotype.[42] Hence, it appears that the MAX-associated tumors fall somewhere in between the cluster 1 and cluster 2 gene expression patterns.