Table 1.
Previously identified mutated driver genes associated with PPGLs.
| Type | Gene | Conding Protein | Chromosome location | Germiline or Somatic | Predominant tumor site | Contribution to metastatic potential | Associated hereditary diseases | Reference |
|---|---|---|---|---|---|---|---|---|
| 1 | SDHA | Succinate Dehydrogenase Complex Flavoprotein Subunit A | 5p15.33 | Germline | PGL>PHEO | Low | Famlilial PGL type 5 | (6, 13), |
| 1 | SDHB | Succinate Dehydrogenase Complex Iron Sulfur Subunit B | 1p36.13 | Germline | PGL>PHEO | Intermediate | Famlilial PGL type 4 | (14) |
| 1 | SDHC | Succinate Dehydrogenase Complex Subunit C | 1q23.3 | Germline | PGL>>PHEO | Very low | Famlilial PGL type 3 | (15) |
| 1 | SDHD | Succinate Dehydrogenase Complex Subunit D | 11q23.1 | Germline | PGL>PHEO | Low | Famlilial PGL type 1 | (6, 16) |
| 1 | SDHAF2 | Succinate Dehydrogenase Complex Assembly Factor 2 | 11q12.2 | Germline | PGL>>PHEO | Very Low | Famlilial PGL type 2 | (17, 36) |
| 1 | FH | Fumarate Hydratase | 1q43 | Germline | PHEO, PGL | Low | FH-deficient HLRCC (Hereditary leiomyomatosis and renal cell carcinoma) | (37) |
| 1 | VHL | Von Hippel-Lindau Tumor Suppressor | 3p25.3 | Germline | PHEO>PGL | Low-Intermediate | Von-Hippel-Lindau disease | (6, 25), |
| 1 | EPAS1 (HIF2A) | Endothelial PAS Domain Protein 1 | 2p21 | Germline, Somatic | PHEO, PGL | Low-Intermediate | Pacak-Zhuang syndrome | (6, 26, 27) |
| 1 | EGLN1 (PHD1) | Egl-9 Family Hypoxia Inducible Factor 1 | 1q42.2 | Germline | PHEO, PGL | Not characterized | Polycythemia | (6, 38) |
| 1 | EGLN2 (PHD2) | Egl-9 Family Hypoxia Inducible Factor 2 | 19q13.2 | Germline | PHEO, PGL | Not characterized | Polycythemia | (38) |
| 1 | MDH2 | Malate Dehydrogenase 2 | 7q11.23 | Germline | PHEO, PGL | Not characterized | Not characterized | (23, 39), |
| 1 | SLC25A11 | Solute Carrier Family 25 Member 11 | 17p13.2 | Germline | PGL | Low-Intermediate | Not characterized | (40) |
| 1 | DLST | Dihydrolipoamide S-Succinyltransferase | 14q24.3 | Germline | PHEO, PGL | Not characterized | Not characterized | (41) |
| 1 | DNMT3A | DNA Methyltransferase 3 Alpha | 2p23.3 | Germline, Somatic | PHEO, PGL | Not characterized | Acute Myeloid Leukemia (AML) (42) | (43) |
| 1 | GOT2 | Glutamic-Oxaloacetic Transaminase 2 | 16q21 | Germline | PHEO, PGL | Not characterized | Not characterized | (44) |
| 2 | CSDE1 | Cold Shock Domain Containing E1 | 1p13.2 | Somatic | PHEO, PGL | Not characterized | ― | (6) |
| 2 | MAML3 | Mastermind Like Transcriptional Coactivator 3 | 4q31.1 | Somatic, Transfusion | PHEO, PGL | Low-Intermediate | ― | (6, 28), |
| 3 | KIF1B | Kinesin Family Member 1B | 1p36.22 | Germline | PHEO? | Not characterized | Ganglioneuroma, leiomyosarcoma, lung adenocarcinoma, neuroblastoma, ganglioneuroma |
(45) |
| 3 | RET | Proto-Oncogene Tyrosine-Protein Kinase Receptor Ret | 10q11.21 | Germline, Somatic | PHEO>>PGL | Low | Multiple endocrine neoplasia type 2 | (6, 29–31), |
| 3 | NF1 | Neurofibromin 1 | 17q11.2 | Germline, Somatic | PHEO>PGL | Low | Nuerofibromatosis type 1 | (6, 29–32), |
| 3 | MAX | MYC Associated Factor X | 14q23.3 | Germline | PHEO>PGL | Low | Familial PCC | (6, 34, 35), |
| 3 | TMEM127 | Transmembrane Protein 127 | 2q11.2 | Germline | PHEO>PGL | Low | Familial PCC | (6, 33), |
| 3 | HRAS | GTPase HRas | 11p15.5 | Somatic | PHEO? | Not characterized | ― | (6) |
| 3 | BRAF | Serine/Threonine-Protein Kinase B-Raf | 7q34 | Somatic | PHEO, PGL | Not characterized | ― | (6) |
| Others | MEN1 | Menin 1 | 11q13.1 | Germline | PHEO, PGL | Not characterized | Multiple endocrine neoplasia type 1 | (46) |
| Somatic | IRP1 | Iron Regulatory Protein 1 | 9p21.1 | Somatic | PHEO, PGL | Not characterized | ― | (47) |
| Somatic | SETD2 | Histone-Lysine N-Methyltransferase SETD2 | 3p21.31 | Somatic | PHEO, PGL | Low-Intermediate | ― | (6, 18, 48), |
| Somatic | FGFR1 | Fibroblast Growth Factor Receptor 1 | 8p11.23 | Somatic | PHEO, PGL | Not characterized | ― | (6, 49), |
| Somatic | MET | Hepatocyte Growth Factor Receptor | 7q31.2 | Somatic | PHEO, PGL | Not characterized | ― | (50) |
| Somatic | TP53 | Cellular Tumor Antigen P53 | 17p13.1 | Somatic, Germline | PHEO, PGL | Not characterized | Li-Fraumeni Syndrome | (6) |
| Somatic | ARNT | Aryl Hydrocarbon Receptor Nuclear Translocator | 1q21.3 | Somatic | PGL | Not characterized | ― | (6) |
| Somatic | MYO5B | Myosin VB | 18q21.1 | Somatic | PHEO, PGL | Not characterized | ― | (51, 52), |
| Somatic | MYCN | N-Myc Proto-Oncogene Protein | 2p24.3 | Somatic | PHEO, PGL | Not characterized | ― | (51) |
| Somatic | VCL | Vinculin | 10q22.2 | Somatic | PHEO, PGL | Not characterized | ― | (51) |
| Somatic | KMT2D | Histone-Lysine N-Methyltransferase 2D | 12q13.12 | Somatic | PHEO, PGL | Not characterized | ― | (53) |
| Somatic | TERT | Telomerase Reverse Transcriptase | 5p15.33 | Somatic | PHEO, PGL | Low-Intermediate | ― | (54–57), |
| Somatic | ATRX | Transcriptional regulator ATRX | Xq21.1 | Somatic | PHEO, PGL | Low-Intermediate | ― | (6, 36, 58–60) |
| Somatic | IDH1 | Isocitrate Dehydrogenase (NADP(+)) 1 | 2q34 | Somatic | PHEO, PGL | Not characterized | ― | (6, 59) |
| Somatic | IDH2 | Isocitrate Dehydrogenase (NADP(+)) 2 | 15q26.1 | Somatic | PHEO, PGL | Not characterized | ― | (61) |
| Somatic | H3F3A | H3 Histone Family Member 3A | 1q42.12 | Somatic | PHEO, PGL | Not characterized | ― | (50) |
Type 1 Pseudohypoxia type, Type 2: Wnt signal type, Type 3: Kinase signal type.
In addition to more than 20 genes with germline mutations, recently detected genes with somatic variants are also summarized in this table. Some genes with somatic variants were classified into three previously known types if the detailed function of the mutated genes was clarified.