New Insights on the Genetics of Pheochromocytoma and Paraganglioma and Its Clinical Implications

Abstract

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors that arise from chromaffin cells. PHEOs arise from the adrenal medulla, whereas PGLs arise from the neural crest localized outside the adrenal gland. Approximately 40% of all cases of PPGLs (pheochromocytomas/paragangliomas) are associated with germline mutations and 30–40% display somatic driver mutations. The mutations associated with PPGLs can be classified into three groups. The pseudohypoxic group or cluster I includes the following genes: SDHA, SDHB, SDHC, SDHD, SDHAF2, FH, VHL, IDH1/2, MHD2, EGLN1/2 and HIF2/EPAS; the kinase group or cluster II includes RET, NF1, TMEM127, MAX and HRAS; and the Wnt signaling group or cluster III includes CSDE1 and MAML3. Underlying mutations can help understand the clinical presentation, overall prognosis and surveillance follow-up. Here we are discussing the new genetic insights of PPGLs.

Co-occurrence of VHL and SDHA Pathogenic Variants: A Case Report

“…Collectively, hereditary paraganglioma-pheochromocytoma (PGL/PCC) syndromes are rare neuroendocrine tumors with an estimated incidence of approximately 2-8 cases per million per year ( 9 ). Approximately 40% of all cases of PGL/PCC are associated with germline pathogenic variants ( 2 , 10 , 11 ) in the pseudo-hypoxic signaling pathway (cluster I), kinase signaling (cluster II), or Wingless and Int-1 (Wnt) signaling group (cluster III) ( Figure 3 ) ( 12 ). Pathogenic variants in the SDHx genes ( SDHA, SDHB, SDHC , and SDHD ) are classified under the cluster I genes which results in dysfunction of succinate dehydrogenase (SDH) leading to competitive inhibition of the enzyme, prolyl hydroxylase, involved in the degradation of hypoxia-inducible factor 1- α (HIF1- α) ( 2 , 13 , 14 ).…”

“…Clinical features include cerebellar and spinal hemangioblastomas, renal cell cancer, neuroendocrine pancreatic tumor, pheochromocytoma, and paragangliomas. Germline pathogenic variants in the succinate dehydrogenase A ( SDHA ) gene are associated with familial paraganglioma and pheochromocytoma syndrome inherited in an autosomal dominant manner ( 2 ). At the cellular level, SDHA and VHL proteins interact and converge into a common molecular pathway via the hypoxia inducible factor alpha (HIF-α) ( 3 ).…”

Bilateral Pheochromocytoma with Germline MAX Variant without Family History

“…Recent studies have indicated that the frequency of germline variants of PPGLs is very high among all human tumors. Besides MAX , multiple new PPGL-related genes such as CSDE1 , H3F3A , MET , MERTK , UBTF-MAML3 , SLC25A11 , IRP1 , DLST , and SUCLG2 have been discovered in recent years [ 35 ]. With the expansion of our knowledge of genetics, new biomarkers and artificial intelligence can also help assess the metastatic risk and overall prognosis of each individual.…”

Principles of molecular testing for hereditary cancer

“…Approximately 5%-10% of all cancers are estimated to be attributable to hereditary cancer syndromes caused by germline variants in cancer predisposition genes, 1,2 however the proportion caused by germline variants varies widely across cancer types (eg, $2%-5% of colorectal cancers, 3 $24% of ovarian cancers, 4 $40% of paragangliomas/ pheochromocytomas 5 ).…”