Genetic bases of pheochromocytoma and paraganglioma

Abstract

The genetics of pheochromocytoma and paraganglioma (PPGL) has become increasingly complex over the last two decades. The list of genes involved in the development of these tumors has grown steadily, and there are currently more than 20 driver genes implicated in either the hereditary or the sporadic nature of the disease. Although genetic diagnosis is achieved in about 75-80% of patients, the genetic aetiology remains unexplained in a significant percentage of cases. Patients lacking a genetic diagnosis include not only those with apparently sporadic PPGL, but also patients with a family history of the disease or with multiple tumors, that meet the criteria to be considered as candidates for carrying germline mutations in yet undiscovered genes. Mutations in known PPGL genes deregulate three main signaling pathways (hypoxia, kinase signaling and wnt-signaling pathways), which could be the starting point for the development of a personalised treatment for PPGL patients. Furthermore, the integration of results from several genomic high-throughput platforms enables the discovery of regulatory mechanisms that cannot be identified by analyzing each piece of information separately. These strategies are powerful tools for elucidating optimal therapeutic options based on molecular biomarkers in PPGL, and represent an important step towards the achievement of precision medicine for patients with metastatic PPGL.

Paraganglioma at the cerebellopontine angle: A case report and review of literature

“…Histopathological examination of the excised tumor revealed a characteristic Zellballen pattern 18 and immunohistochemical analysis served as standardized validation for the neuroendocrine tumor 1 . Genetically, PGLs can be sporadic and hereditary 19 . The Cancer Genome Atlas categorized patients of PGLs into three distinct disease clusters: pseudo‐hypoxic, Wnt‐signaling, and kinase‐signaling 1,19 .…”

“…The Wnt‐signaling pathway regulates various developmental processes, such as cell proliferation and differentiation. In PGLs associated with the Wnt‐altered subtype, there are mutations in the CSDE1 (cold shock domain containing E1) and MAML3 genes (mastermind‐like transcriptional coactivator 3) 19 . Both mutations contribute toward the abnormal cell proliferation and metastasis in PGLs.…”

Lesion-based indicators predict long-term outcomes of pheochromocytoma and paraganglioma– SIZEPASS

“…During the three decades since the mapping of the MEN2 locus to chromosome 10 (41), multi-omics definition of principal driver lesions (42), recognition of key aberrations in DNA repair altering lesion evolution (43), and a growing approach including alterations in mitochondrial genes (44,45), have created an increasingly complex and complete, yet imperfect, picture of genetic causation. When the majority of PPGLs was considered sporadic in 1990, this group has shrunk to merely 30-50% at present (9,46); and it may shrink further. Assessment of a majority of currently available genetic targets has considerable complexity, and the ever-novel immunohistochemical tests are by no means cheap.…”

Tumor metabolism in pheochromocytomas: clinical and therapeutic implications

“…Individuals with germline SDHB mutations have an increased susceptibility to malignant tumors due to their genetic makeup [ 45 , 65 ]. FH [ 66 ], MAX [ 67 ], SDHD [ 68 ], SLC25A11 [ 69 ], and telomerase reverse transcriptase ( TERT ) [ 70 , 71 ] mutations as well as MAML3 gene fusion [ 72 ] have been identified in malignant PPGLs. An additional risk factor for the clinical development of PPGL is the aggressive phenotype that is linked to somatic mutations of alpha-thalassemia/mental retardation syndrome X-linked ( ATRX ) [ 73 , 74 ].…”