Table 3.
PPGL susceptibility genes
| Gen | Syndrome | Biochemical profile | Year of discovery | Gene role | Clinical presentation | Mutation type | Cluster | Inheritance | References |
|---|---|---|---|---|---|---|---|---|---|
| NF1 | Neurofibromatosis Type 1 | Adrenergic | 1990 | TSG: ↓ cell proliferation by blocking RAS/RAF/MAPK and PI3K/AKT/mTOR pathways |
Hallmark signs: Café-au-lait Macules (99% within first year of llife), Skinfold freckling (Crowe's sign), Cutaneous neurofribromas, lysch nodules, optic glioma Xanthogranuloma, melanoma (0.1–5.4%), skeletal manifestations (such as scoliosis or macrocephaly), astrocytoma, PPGL, GIST, malignant schwannoma, juvenile myelomonocytic leukemia |
G | 2 | AD | [134] |
| RET | MEN 2 | Adrenergic | 1993 | Proto-oncogene: encodes TKR; which once bound to GTNF activates the RAS/RAF/ERK-signaling pathway, leading to cell proliferation and invasiveness | PCC 50–100% MTC, PCC, HPT, cutaneous amyloidosis, Hirschsprung disease, mucosal neuroma, dysmorphic and, marphanoid features | G | 2 | AD | [134] |
| VHL | von Hippel-Lindau | Noradrenergic | 1993 | TSG: ↑HIF2A degradation under HYPOXIA conditions | PPGL 10–20%. Hemangioblastoma (cerebellar, spinal cord, retina), RCC, pNET, pancreatic cysts, yolk sac tumor | G | 1 | AD | [134] |
| MEN1 | MEN 1 | Adrenergic | 1993 | TSG: Regulates transcription, stabilizes genome y ↓ cell proliferation |
Parathyroid adenoma, pNET, gastrinoma, pituitary adenomas, adrenal tumor, other carcinoids, lipoma, angiofibroma, meningioma PCC < 1% |
G | 2 | AD | [134] |
| SDHD | Familial PPGL linked to SDHD | Noradrenergic | 2000 | TSG: encodes SDH that catalyzes the oxidation of succinate to fumarate in the TCA cycle. Increase in succinate leads to stabilization of HIF | ↑Penetrance PPGL (> 80%), GIST, pituitary adenomas | G | 1 | AD*** | [134] |
| SDHC | Familial PPGL linked to SDHC | 2000 | ↓↓Penetrance PPGL; other tumor: pituitary adenoma; GIST | G | 1 | AD | [135] | ||
| SDHB | Familial PPGL linked to SDHB | 2001 | Malignant PPGL, penetrance ~ 16–22 and 44%, at 50, 60 and 80 years respectively, RCC (4.2%), GIST, pituitary adenomas | G | 1 | AD | [134] | ||
| SDHAF2 | Familial PPGL linked to SDHAF2 | 2009 | Unknown penetrance | G | 1 | AD*** | [136] | ||
| SDHA | Familial PPGL linked to SDHA | 2010 | ↓Penetrance PPGL, GIST | G | 1 | AD | [137] | ||
| TMEM127 | Adrenergic | 2010 | TSG: ↓ cell proliferation by blocking PI3K/AKT/mTOR pathways | ↓↓Penetrance PPGL; other tumors: RCC | S | 2 | N/A | [31] | |
| IDH1 | Noradrenergic | 2010 | TSG: catalyzes the oxidative decarboxylation of isocitrate in the TCA cycle. Increase in α-ketoglutarate leads to stabilization of HIF | ↓↓Penetrance PPGL | S | 1 | N/A | [138] | |
| IDH2 | 2010 | S | 1 | N/A | [139] | ||||
| MAX | Noradrenergic Adrenergic | 2011 | TSG: ↓ cell proliferation, regulator of differentiation ↑ apoptosis | Mainly PCC | S | 2 | AD; paternal transmission | [140] | |
| FH | HLRCC | Noradrenergic | 2012 | TSG; encodes FH that catalyzes the reversible hydration of fumarate to l-malate in the TCA cycle. Increase in fumarate leads to stabilization of HIF | Multifocal PPGL, metastatic, associated HLRCC or MCUL | G | 1 | AD | [33, 141] |
| HIF2A or EPAS1 | Pacak-Zhuang | Noradrenergic | 2012 | Oncogene; encodes EPAS1; transcription factor related to oxygen-level responses and activated in hypoxic conditions | Triad of PPGLs, polycythemia, and somatostatinoma. Ocular abnormalities occur in 70% | S/M | 1 | N/A | [142–145] |
| H-RAS | Adrenergic | 2013 | Proto-oncogene; encodes H-RAS, which once bound to GTP activates the RAS/RAF/ERK-signaling pathway, leading to cell proliferation | Mainly single PCC (Caucasian population), sporadic, mainly benign | S | 2 | N/A | [146, 147] | |
| H3F3A | Unknown | 2013 | Encodes the histone H3.3 protein that has an essential role in maintaining genome integrity during mammalian development | Giant cell tumors of the bones (GCT), PCCs, bladder and periaortic PPGL | S/M | * | N/A | [148] | |
| EGLN2 | Noradrenergic | 2015 | TSG; encodes PHD1, an enzyme that, in normal oxygen conditions, hydroxylates specific proline residues of the HIF-α subunits for posterior degradation in the proteasome | Polycythemia associated with recurrent PPGLs, and normal or mild elevated EPO | G | 1 | ** | [149] | |
| MDH2 | Noradrenergic | 2015 |
TSG; encodes MDH2, which catalyzes the reversible oxidation of malate to oxaloacetate in the TCA cycle Increase in malate, fumarate and succinate leads to stabilization of HIF |
Multiple PGLs, metastatic | G | 1 | AD | [150] | |
| ATRX | 2015 | Encodes a chromatin remodeling protein that regulates the nuclear matrix and chromatin association | Clinically more aggressive and metastatic PGL | S | * | N/A | [151] | ||
| CSDE1 | Noradrenergic | 2017 | TSG. Involved in normal development through messenger RNA stability internal initiation of translation, and cell-type-specific apoptosis. Promotes and represses the translation of RNAs and also increases and decreases the abundance of RNAs | Sporadic, metastatic, recurrent PPGL | S | 3 | N/A | [34] | |
| MAML3 | Noradrenergic | 2017 | Oncogene. Encodes a transcriptional coactivator for NOTCH. In PPGLs, with a hypomethylated profile ⟶ mRNA overexpression of the target gene involved in Wnt receptor and Hedgehog signaling pathways | Sporadic, recurrent PGL. New prognostic factor of poor outcome | F | 3 | N/A | [34] | |
| IRP1 | Noradrenergic | 2018 | TSG; encodes IRP1, which controls cellular iron metabolism and negatively regulates HIF2α mRNA translation under iron-deficient conditions. Deficiency of IRP1 protein increases HIF2α | Sporadic, adrenal PCC | S | 1 | N/A | [152] | |
| SLC25A11 | Noradrenergic | 2018 | TSG: encodes the mitochondrial 2-oxoglutarate/malate carrier in the TCA cycle leading to stabilization of HIF | Malignant PPGL, HNPGL | G | 1 | AD | [36] | |
| DLST | Noradrenergic | 2019 | TSG: encodes the E2 subunit of the mitochondrial αKG dehydrogenase (OGDH). Depletion of any of the OGDH complex subunits leads to impaired enzymatic activity, a-ketoglutarate accumulation and stabilization of HIF |
Recurrent multiple PPGLs, malignancy also described, pituitary adenoma, uterine carcinoma also described PPGL >> PCC |
G | 1 | AD | [35] |
AD Autosomal Dominant, AKT serine/threonine kinase, ATRX chromatin remodeler ATRX, CRG growth regulatory factors, CSDE1 coldshock domain containing E1, DLST Dihydrolipoamide S-Succinyltransferase, EGLN1/2 egl nine homolog 1 and 2, EPAS1 PAS domain-containing protein 1, EPO erythropoietin, ERK extracellular mitogen-activated protein kinase 1, F fusion, FH fumarate hydratase, GTNF glial cell line‐derived neurotrophic factor, HNPGL head and neck paraganglioma, G germline, GTC giant cell tumor of the bone, H3F3A H3 histone family member 3A, HIF2α hypoxia-inducible factor 2 alpha, HIF2A hypoxia-inducible factor 2 alpha, HLRCC leiomyomatosis and renal cell cancer, H-RAS HRAS proto-oncogene, IDH1/2 isocitrate dehydrogenase 1 and 2, IRP1 iron regulatory protein, M mosaicism, MCUL multiple cutaneous leiomyomatosis, MDH1/2 malate dehydrogenase type 1 and 2, MAML3 coactivator 3 mastermind-like, MAPK, mitogen-activated protein kinase; MAX, myc-associated factor X gene; Men1, multiple endocrine neoplasia 1; MEK, mitogen-activated protein kinase; mRNA, messenger ribonucleic acid; mTOR, mammalian target of rapamycin; N/A, Not Applicable in the setting of somatic mutations; NETs, neuroendocrine tumors; NF1, neurofibromin 1; PCC, pheochromocytoma; PGLs, paraganglioma; PHD1/2, prolyl hydroxylase 1 and 2; PI3K, phosphatidyl-inositol-3-kinase; PPGL, pheochromocytoma-paraganglioma; RCC, renal cell carcinoma; S, somatic; SLC25A11, Solute Carrier Family 25 Member 11; SDH, succinate dehydrogenase subunits A/B/C/D; SDHAF2, succinate dehydrogenase complex assembly factor 2; TCA, tricarboxylic acid, TFG, transcription factors genes; TKR, tyrosine kinase receptor; TMEM127, transmembrane protein 127; TSG, tumor suppressor gene; VHL, von Hippel Lindau
*Not classified by clusters, **Unknown, ***maternal imprinting