04.12.2020

EPAS1 Mutations and Paragangliomas in Cyanotic Congenital Heart Disease

Pheochromocytomas and paragangliomas are catecholamine-secreting tumors of chromaffin cells with frequent germline, somatic, or postzygotic mutations in genes that are involved in hypoxia-related pathways (including VHL, SDHA, SDHB, SDHC, SDHD, SDHAF2, EGLN1, FH, MDH2, and EPAS1).

These mutations result in aberrant and constitutive activation of hypoxia-inducible factors (HIFs) even under normal levels of oxygen, a condition known as pseudohypoxia.1 Beyond genetic causes, prolonged exposure to hypoxia has been reported as an environmental risk factor for pheochromocytomas and paragangliomas that arise in persons living at high altitude.2 We previously found that patients who have chronic hypoxemia that is due to cyanotic congenital heart disease were at increased risk for pheochromocytomas and paragangliomas,3 but the mechanism underlying this association is unclear.

Table 1. Clinical and Biochemical Features of Five Patients Presenting with Cyanotic Congenital Heart Disease and Pheochromocytomas or Paragangliomas (PPGL), with EPAS1 Mutation Status.

Here we report the identification of gain-of-function somatic mutations of EPAS1, which encodes for HIF-2α, in pheochromocytomas and paragangliomas in four of five patients (80%) who presented with cyanotic congenital heart disease. The clinical and genetic details of the patients are shown in Table 1, and in the Supplementary Appendix (available with the full text of this letter at NEJM.org). The affected residues, 530 and 531, are known to regulate HIF-2α stability and, when mutant, result in constitutive HIF-2α activation and tumor growth in vivo.4,5

Given the relatively young age of patients presenting with cyanotic congenital heart disease and pheochromocytomas and paragangliomas, an inherited susceptibility to pheochromocytomas and paragangliomas would be expected to account for most cases.1 However, no other germline pathogenic mutations or other syndromic tumors that have been associated with pheochromocytomas and paragangliomas were found in these five patients (see the Supplementary Appendix). In contrast, each of the mutations in the present series was somatic.

The high frequency of mutations of EPAS1 in these samples (80%) contrasts with rates of only 5 to 6% in cohorts of unselected patients with pheochromocytomas and paragangliomas,1 which argues for a causative role for the EPAS1 mutations in the development of pheochromocytomas and paragangliomas that arise in patients with cyanotic congenital heart disease. These observations, along with the existence of a clear link between pheochromocytomas and paragangliomas with mutations that lead to the activation of HIFs and cellular pseudohypoxia, suggest an exquisite sensitivity of chromaffin cells to HIF-2α–mediated growth. It is possible that the EPAS1 mutations endow chromaffin cells that have been exposed to chronic hypoxia with the ability to amplify the oncogenic properties of HIF-2α.

Anand Vaidya, M.D.
Brigham and Women’s Hospital, Boston, MA

Shahida K. Flores, M.Sc.
Zi-Ming Cheng, M.D.
Marlo Nicolas, M.D.
Yilun Deng, M.D., Ph.D.
University of Texas Health Science Center at San Antonio, San Antonio, TX

Alexander R. Opotowsky, M.D.
Boston Children’s Hospital, Boston, MA

Delmar M. Lourenço, Jr., M.D., Ph.D.
University of São Paulo, São Paulo, Brazil

Justine A. Barletta, M.D.
Brigham and Women’s Hospital, Boston, MA

Huma Q. Rana, M.D.
Dana–Farber Cancer Institute, Boston, MA

M. Adelaide Pereira, M.D., Ph.D.
University of São Paulo, São Paulo, Brazil

Rodrigo A. Toledo, Ph.D.
Vall d’Hebron Institute of Oncology, Barcelona, Spain

Patricia L.M. Dahia, M.D., Ph.D.
University of Texas Health Science Center at San Antonio, San Antonio, TX
dahia@uthscsa.edu

Supported by grants from the National Institutes of Health (NIH) (DK107407, to Dr. Vaidya; GM114102, to Dr. Dahia), by a grant from the Doris Duke Charitable Foundation (2015085, to Dr. Vaidya), by a National Research Service Award Institutional Predoctoral Training Grant (T32CA148724, to Ms. Flores), by a Cancer Prevention and Research Institute of Texas (CPRIT) Training Grant (RP140105, to Dr. Deng), by a São Paulo Research Foundation (FAPESP) grant (2016/07504-2, to Dr. Lourenço), by a Miguel Servet-I research contract from the Institute of Health Carlos III of the Ministry of Economy and Competitiveness (CP17/00199, to Dr. Toledo), by the Olga Torres Foundation (to Dr. Toledo), by a CPRIT Individual Investigator Award (RP140473, to Dr. Dahia), and by the Greehey Children’s Cancer Research Institute (GCCRI) (to Dr. Dahia). The GCCRI Genomic Sequencing Facility is supported by a grant (P30-CA54174, to the Cancer Therapy and Research Center at the University of Texas Health Science Center at San Antonio) and by an NIH Shared Instrument grant (1S10OD021805-01).

Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.

Dr. Vaidya and Ms. Flores contributed equally to this letter.

Author Affiliations

  1. 1. Dahia PL. Pheochromocytoma and paraganglioma pathogenesis: learning from genetic heterogeneity. Nat Rev Cancer 2014;14:108-119.
  2. 2. Astrom K, Cohen JE, Willett-Brozick JE, Aston CE, Baysal BE. Altitude is a phenotypic modifier in hereditary paraganglioma type 1: evidence for an oxygen-sensing defect. Hum Genet 2003;113:228-237.
  3. 3. Opotowsky AR, Moko LE, Ginns J, et al. Pheochromocytoma and paraganglioma in cyanotic congenital heart disease. J Clin Endocrinol Metab 2015;100:1325-1334.
  4. 4. Zhuang Z, Yang C, Lorenzo F, et al. Somatic HIF2A gain-of-function mutations in paraganglioma with polycythemia. N Engl J Med 2012;367:922-930.
  5. 5. Toledo RA, Qin Y, Srikantan S, et al. In vivo and in vitro oncogenic effects of HIF2A mutations in pheochromocytomas and paragangliomas. Endocr Relat Cancer 2013;20:349-359.

Table 1.

Clinical and Biochemical Features of Five Patients Presenting with Cyanotic Congenital Heart Disease and Pheochromocytomas or Paragangliomas (PPGL), with EPAS1 Mutation Status.*

Patient No. and Age Description of Cyanotic Congenital Heart Disease and Treatment Features at PPGL Diagnosis Catecholamines† PPGL Locationand Size EPAS1 Genotype
Sao2‡ Hematocrit Symptoms Tumor Germline
% %
1, 48 yr Tricuspid and pulmonary atresia, ASD, and VSD

Treatment: Potts shunt at 5 mo of age; right BTS at 5 yr

79 64.4 Paroxysmal atrial fibrillation, diaphoresis, hypertension, anxiety, palpable neck mass P-NMN, 14×;
P-MN, 2×
Left adrenal PHEO, 3.0cm×4.0 cm; right carotid body PGL, 1.2 cm×1.7 cm c.1591C→T, p.Pro531Ser in PHEO; WT in PGL NA§
2, 13 yr Pulmonary atresia, double-outlet right ventricle, common atrioventricular canal defect, ASD, and VSD

Treatment: left BTS at 3 days of age; central shunt at 7 yr; Kawashima, left pulmonary arterioplasty, atrioventricular valvuloplasty, and central shunt closure at 17 yr

85 55.0 Hypertension, diaphoresis, palpitations, dyspnea P-NMN, 5×;
P-MN, normal
Left adrenal PHEO, 6.4cm×5 cm c.1588G→C, p.Ala530Pro WT
3, 23 yr Tricuspid atresia with “normally related greater arteries” and pulmonary stenosis and bilateral SVC

Treatment: Left BTS at 4 mo of age; bidirectional Glenn shunt at 2 yr; lateral tunnel fenestrated Fontan procedure at 3 yr; fenestration-device closure at 16 yr; ICD for cardiac arrest at 20 yr

92 47.3 Hypertension, diaphoresis P-NMN, 11×;
P-MN, normal
Abdominal periaortic PGL, 2.9cm×2.7 cm c.1592C→G, p.Pro531Arg WT
4, 21 yr Heterotaxy syndrome with polysplenia, double-outlet right ventricle, right dominant atrioventricular canal defect, hypoplastic left ventricle, interrupted IVC, and AVM in left lung

Treatment: pulmonary-artery banding at 2 wk of age; bilateral Glenn shunt and fenestrated intraatrial baffling of hepatic veins to right pulmonary artery at 2 yr; pulmonary valvectomy and closure of baffle fenestration at 4 yr

77 50.9 Syncope, diaphoresis, dyspnea, chest pain, headaches P-NMN, 30×;
P-MN, normal
Right adrenal PHEO, 4.3cm×4.0cm c.1591C→T, p.Pro531Ser WT
5, 54 yr Tetralogy of Fallot with pulmonary stenosis

Treatment: Potts shunt at 8 mo of age; intracardiac repair at 9 yr; aortobifemoral bypass for PAD at 38 yr; PVR, tricuspid-valve repair, and left pulmonary arterioplasty at 48 yr; ICD for NSVT at 52 yr

92 39.7 Hypertension, diaphoresis, palpitations P-NMN, 23×;
P-MN, <2×
Abdominal periaortic PGL, 6.3cm×5.8 cm WT WT

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