Pheochromocytoma: A Genetic and Diagnostic Update

Leilani B. Mercado-Asis, MD, PhD, MPH; Katherine I. Wolf; Ivana Jochmanova, MD; David Taïeb, MD


Endocr Pract. 2018;24(1):78-90. 

In This Article

Genes Involved in PPGL Tumorigenesis

Most PPGLs can be ascribed to either germline (~40%) or somatic mutations (~30%).[11–13] Mutations in more than 19 genes involved in tumorigenesis were discovered in PPGLs, of which at least 12 are associated with a syndromic PPGL presentation (Table 1). PPGL susceptibility genes are divided into 2 clusters: Cluster 1 is pseudohypoxic, and Cluster 2 is rich in kinase signaling.

Cluster 1 breaks into Cluster 1a, which contains genes encoding Krebs cycle enzymes: mitochondrial succinate dehydrogenase complex (SDHx: SDHA, SDHB, SDHC, SDHD), the SDH complex assembly factor 2 (SDHAF2), fumarate hydratase (FH), malate dehydrogenase 2 (MDH2), and isocitrate dehydrogenase (IDH). Cluster 1b consists of the von Hippel-Lindau (VHL) tumor suppressor gene, hypoxia-inducible factor 2α (EPAS1/HIF2A), egl-9 family hypoxia inducible factor 2 (EGLN2/PHD1), and factor 1 (EGLN1/PHD2); these are reviewed in detail elsewhere.[13] Tumors harboring mutations in Cluster 1 genes are highly vascularized and overexpress vascular endothelial growth factor (VEGF) and VEGF receptors,[14] which is a part of the pseudohypoxic signature.

Patients with somatic mutations in EPAS1/HIF2A present with a new syndrome of PPGLs with or without erythrocytosis and/or somatostatinomas.[15,16] Novel EGLN1 and EGLN2 mutations were also identified in patients presenting with PPGLs and erythrocytosis without EPAS1/HIF2A mutations.[17]

PPGLs associated with the second cluster have mutations in genes involved in kinase receptor signaling: the RET proto-oncogene, neurofibromin 1 (NF1), transmembrane protein 127 (TMEM127), MYC-associated factor X (MAX), kinesin family member 1B (KIF1B), HRas proto-oncogene (HRAS), and ATRX chromatin remodeler (ATRX). Dysregulation of kinase signaling pathways such as phosphoinositide 3-kinase (PI3K)/AKT or mammalian target of rapamycin (mTOR), results in the activation of pathways involved in oncogenic processes (reviewed in[13,18,19]).

Focus has now shifted to try and understand PPGL pathogenesis and identify similarities in metabolic changes for PPGLs with different genetic backgrounds. Data indicates that dysregulation of metabolism in both PPGL clusters are linked through activation of the hypoxia signaling pathway.[18] Tumor hypoxia/pseudohypoxia is supposed to have a direct oncogenic or tumor suppressive effect via regulation of various cellular processes. Hypoxia-inducible factors (HIFs) are key players in cellular responses to hypoxia, and the PHD2-VHL-HIF2α pathway is critical for erythropoiesis. Partial disturbances in this pathway are associated with erythrocytosis, while substantial changes are involved in tumorigenesis[17] (reviewed in[19]). Novel EPAS1/HIF2A[15,20] and EGLN1/2[17,21,22] mutations identified in PPGLs strongly favor hypoxia signaling as one of the key pathways involved in PPGL development.

The HIF signaling pathway can be triggered by many other oxygen-independent impulses (reviewed in[18]). In PPGLs, HIF activation occurs (1) when genes directly involved in regulation of hypoxic responses are mutated (Cluster 1 genes), or (2) when mutations in genes involved in the mTOR and PI3K signaling pathways (Cluster 2 genes) indirectly trigger activation (reviewed in[18]).

Several genes have been implicated in PPGL aggressiveness. Sporadic gene mutations related to chromatin remodeling have been described.[23,24] For instance, the ATRX gene is involved in telomere maintenance and chromosome integrity,[25] as well as in gene expression and transcriptional repression of noncoding telomeric repeat-containing RNA (TERRA).[26] Somatic ATRX mutations were identified in 12.6% of PPGLs, and these mutations are associated with alternative telomere lengthening and more aggressive tumor behavior.[23] Mutation of the histone 3.3-encoding gene (H3F3A) was discovered in a patient who presented with a recurrent giant cell tumor of the tibia and as bilateral PPGL, suggesting that the H3F3A mutation was inherited as a driver event in these tumors.[24]

Recently, novel CSDE1 mutations and MAML3 fusion genes were described as important molecular alterations in PPGL tumorigenesis.[27]CSDE1 seems to act as a tumor suppressor, although further elucidation of its function is needed. PPGLs harboring MAML3 fusions (with UBTF or TCF4) are associated with a specific expression phenotype: Wnt signaling pathway activation, DNA hypomethylation, and poor clinical outcome.[27]

PPGLs display a high rate of inherited gene mutations. New data indicate that there are certain genotype-phenotype correlations, including a higher risk of metastatic disease development. Therefore, genetic testing should be considered in all PPGL patients, and it is strongly recommended in patients with a family history of the disease or relatives of PPGL susceptibility gene mutation carriers.[28] PPGL patients diagnosed at a young age, those that present with multiple or bilateral adrenal tumors, and those with metastatic disease should also seek genetic evaluation.[29] Early identification of an underlying genetic mutation can help predict the disease course and guide treatment strategy. Clinical and biochemical phenotypes can serve as a tool for routing genetic testing (Table 2). Therefore, a comprehensive personal and family history, as well as clinical and biochemical evaluation are essential for prioritizing testing for specific genes. Genetic counseling for patients harboring germline mutations is essential to explain the potential consequences and course of their disease. Typically, in patients with a known PPGL family history and an associated mutation, only the known mutation needs to be analyzed. In syndromic presentations such as with neurofibromatosis type 1, von Hippel-Lindau disease, or multiple endocrine neoplasia, genetic testing should primarily focus on the genes associated with that particular phenotype.[1,30]

The presence of metastatic disease indicates the possibility of SDHB or FH mutations. Familial forms of PPGL usually show autosomal dominant inheritance—children of mutation carriers have a 50% chance of inheriting the mutation from their parent. However, in certain mutations, for example SDHx, negative family history does not rule out the presence of a familial form of PPGL because of the low penetrance of the disease. SDHD, SDHAF2, and MAX mutations are maternally imprinted; thus, the disease will develop only if the mutated gene is inherited paternally. Germline mutations also can occur de novo (reviewed in[30]).

The biochemical phenotype of PPGL can also serve as a lead in to genetic testing. The 3 basic PPGL biochemical profiles include: adrenergic (epinephrine/metanephrine [MN]), noradrenergic (norepinephrine/normetanephrine [NMN]), and dopaminergic (dopamine/methoxytyramine [MTY]). Mixed phenotypes are common and in such cases, MN and NMN secretion is considered to be adrenergic, whereas NMN and MTY production is considered dopaminergic. Adrenergic mixed phenotype is associated with NF1, RET, KIF1Bβ, and MAX mutations. TMEM127-mutated tumors are solely adrenergic. Extra-adrenal dopaminergic and/or noradrenergic PPGLs usually suggest mutations in SDHx, SDHAF2, HIF2A, FH, IDH, and PHD1/2 genes. VHL and HIF2A-mutated PPGLs are typically noradrenergic, and SDHx tumors exhibit a dopaminergic component.[30]