Abstract
Endothelial PAS domain-containing protein 1 (EPAS1) is an oxygen-sensitive component of the hypoxia-inducible factors (HIFs) having reported implications in many cancers by inducing a pseudo-hypoxic microenvironment. However, the molecular dysregulation and clinical significance of EPAS1 has never been investigated in depth in phaeochromocytomas/paragangliomas. This study aims to identify EPAS1 mutations and alterations in DNA copy number, mRNA and protein expression in patients with phaeochromocytomas/paragangliomas. The association of molecular dysregulations of EPAS1 with clinicopathological factors in phaeochromocytomas and paragangliomas were also analysed. High-resolution melt-curve analysis followed by Sanger sequencing was used to detect mutations in EPAS1. EPAS1 DNA number changes and mRNA expressions were examined by polymerase chain reaction (PCR). Immunofluorescence assay was used to study EPAS1 protein expression. In phaeochromocytomas, 12% (n = 7/57) of patients had mutations in the EPAS1 sequence, which includes two novel mutations (c.1091A>T; p.Lys364Met and c.1129A>T; p.Ser377Cys). Contrastingly, in paragangliomas, 7% (n = 1/14) of patients had EPAS1 mutations and only the c.1091A>T; p.Lys364Met mutation was detected. In silico analysis revealed that the p.Lys364Met mutation has pathological potential based on the functionality of the protein, whereas the p.Ser377Cys mutation was predicted to be neutral or tolerated. The majority of the patients had EPAS1 DNA amplification (79%; n = 56/71) and 53% (n = 24/45) patients shown mRNA overexpression. Most of the patients with EPAS1 mutations exhibited aberrant DNA changes, mRNA and protein overexpression. In addition, these alterations of EPAS1 were associated with tumour weight and location. Thus, the molecular dysregulation of EPAS1 could play crucial roles in the pathogenesis of phaeochromocytomas and paragangliomas.
Highlights
Phaeochromocytomas and paragangliomas are rare catecholamines producing neural crest tumours derived from neuroendocrine chromaffin cells [1]
Genetic alterations in the endothelial PAS domain-containing protein 1 (EPAS1) sequence were noted in 12% (7/57) of phaeochromocytoma tumours (Table 1)
In the present study, we have noted that the patients with phaeochromocytoma/paraganglioma having EPAS1 mutations had no mutations in phaeochromocytoma/paraganglioma-susceptible gene panels except NF1 in two patients with Neurofibromatosis 1
Summary
Phaeochromocytomas and paragangliomas are rare catecholamines producing neural crest tumours derived from neuroendocrine chromaffin cells [1]. Phaeochromocytoma arises in the adrenal gland and paraganglioma in extra-adrenal chromaffin cells outside the adrenal gland [2,3]. The most common extra-adrenal location of this tumour is in the carotid body [3,4]. As the behaviour of this group of tumours is difficult to predict, the World Health Organization classified the tumours as metastasizing and non-metastasizing (instead of benign and malignant) [5]. The genetics of phaeochromocytomas and paragangliomas is complex. 40% of phaeochromocytomas/paragangliomas are familial and part of different hereditary syndromes such as multiple endocrine neoplasia type 2 (MEN2), von Hippel-Lindau disease (VHL), neurofibromatosis type
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