Tumoral EPAS1 (HIF2A) mutations explain sporadic pheochromocytoma and paraganglioma in the absence of erythrocytosis

Abstract

Pheochromocytomas (PCCs) and paragangliomas (PGLs) are chromaffin-cell tumors that arise from the adrenal medulla and extra-adrenal paraganglia, respectively. The dysfunction of genes involved in the cellular response to hypoxia, such as VHL, EGL nine homolog 1, and the succinate dehydrogenase (SDH) genes, leads to a direct abrogation of hypoxia inducible factor (HIF) degradation, resulting in a pseudo-hypoxic state implicated in PCC/PGL development. Recently, somatic post-zygotic mutations in EPAS1 (HIF2A) have been found in patients with multiple PGLs and congenital erythrocytosis. We assessed 41 PCCs/PGLs for mutations in EPAS1 and herein describe the clinical, molecular and genetic characteristics of the 7 patients found to carry somatic EPAS1 mutations; 4 presented with multiple PGLs (3 of them also had congenital erythrocytosis), whereas 3 were single sporadic PCC/PGL cases. Gene expression analysis of EPAS1-mutated tumors revealed similar mRNA EPAS1 levels to those found in SDH-gene- and VHL-mutated cases and a significant up-regulation of two hypoxia-induced genes (PCSK6 and GNA14). Interestingly, single nucleotide polymorphism array analysis revealed an exclusive gain of chromosome 2p in three EPAS1-mutated tumors. Furthermore, multiplex-PCR screening for small rearrangements detected a specific EPAS1 gain in another EPAS1-mutated tumor and in three non-EPAS1-mutated cases. The finding that EPAS1 is involved in the sporadic presentation of the disease not only increases the percentage of PCCs/PGLs with known driver mutations, but also highlights the relevance of studying other hypoxia-related genes in apparently sporadic tumors. Finally, the detection of a specific copy number alteration affecting chromosome 2p in EPAS1-mutated tumors may guide the genetic diagnosis of patients with this disease.

Consensus Statement on next-generation-sequencing-based diagnostic testing of hereditary phaeochromocytomas and paragangliomas

“…The EPAS1 gene was found to be somatically mutated in PPGLs and in patients who had an association between these tumours and polycythaemia and/or, rarely, duodenal somatostatinomas 19,[75][76][77] . Further studies have demonstrated that these mutations can be mosaic, and are occasionally detected in non-tumorous tissue at a low frequency 78 .…”

GEP- NETS UPDATE: Genetics of neuroendocrine tumors

“…The recently recognized polycytemia and PGL syndrome was shown to occur as a result gain of function mutations in EPAS1 that resulted in a pseudohypoxic state through reduction in HIF2a degradation mediated by disturbed VHL binding (43,70,71,72). The mode of inheritance for the polycytemia and PGL syndrome (OMIM 603349) is currently unknown due to near exclusive presentation in mosaicism.…”

Polycythemia and Paraganglioma With a Novel Somatic HIF2A Mutation in a Male

“…Four patients presented with pheochromocytomas and paragangliomas associated with polycythemia. 9,10 In the present case, after surgery, the patient had a persistent although much lower elevation of plasma norepinephrine (904-1055 pg/mL). Therefore, he should be screened for the presence of somatostatinomas and pheochromocytomas, as well as residual and recurrent paragangliomas.…”