(CSEMP041) GENETIC CHARACTERIZATION OF A CASE OF PHEOCHROMOCYTOMA IN A PULMONARY TRANSPLANT PATIENT

Abstract:

Background: Approximately 40% of PPGL patients carry germline mutations in susceptibility genes. An association was described between hypoxemia and PPGLs, notably in higher altitude exposition and cyanotic congenital heart disease. In the latter, a chronic hypoxemic state can lead to gain of function somatic mutations in the EPAS1 gene that encodes for hypoxia-inducible factor 2-alpha (HIF-2α) (1).

Objective: To describe and characterize the genetic background of a rare case of PHEO in a pulmonary transplant patient.
Clinical

Case: A 66 year-old man underwent lung transplant at 47 yo for chronic obstructive pulmonary disease. He required home oxygen therapy for 3 years prior to transplant and was known for new onset diabetes after transplant and hypertension. Nineteen years after transplant, a thoracic CT-scan showed a 6.1x 3.9 cm right adrenal mass (HU of 7). Diagnosis of PHEO was confirmed biochemically (noradrenaline 713 nmol/d (N < 650), adrenaline 588 nmol/d (N < 145), normetanephrines 900 nmol/d (N < 600) and metanephrines 1191 nmol/d (N < 370)). Chromogranin A was elevated (3297 ng/mL (N < 104)). The adrenal mass showed no uptake at 18F-FDG PET/CT imaging but fixation at MIBG scintigraphy. The patient received alpha blockers and underwent a laparoscopic right adrenalectomy. The pathology confirmed a PHEO with a PASS score of 8 to 10. Eighteen months following the surgery, the patient showed no signs of recurrence.
Genetic studies: 1) Germline PPGL multigene panel: After consent, the patient underwent a panel of 14 susceptibility genes for PPGLs (INVITAE, CA, USA) that revealed no pathogenic variants. 2) Somatic genetic analysis for EPAS1 gene: PHEO DNA was extracted and exons 9, 12 and 16 of the EPAS1 gene were studied by Sanger Sequencing. No pathogenic variants were identified. 3) RNA-sequencing: RNA-sequencing of patient tumoral DNA was performed and showed an overexpression of HIF-2α compared to reference samples.

Conclusion: We report a rare case of PHEO in a pulmonary transplant patient. Our genetic analyses demonstrated the absence of a pathogenic germline variant in known susceptibility PPGL genes and no somatic mutations in the EPAS1 gene, but revealed overexpression of HIF-2α. The mechanism underlying this phenomenon is still unclear. Further work is needed to better understand the genetic and molecular events leading to PHEO in this specific case and determine its possible relationship with hypoxemia.

(1) Vaidya A and al. . EPAS1 Mutations and Paragangliomas in Cyanotic Congenital Heart Disease. New England Journal of Medicine. 2018;378(13):1259-61