PS-BPR01-7: CONCURRENT SOMATIC MUTATIONS IN CTNNB1 AND GNA11 IN AN ALDOSTERONE-PRODUCING ADENOMA

Abstract

Background: Aldosterone-producing adenoma (APA) is a major subtype of primary aldosteronism (PA), a common form of secondary hypertension. In the past decade, there has been significant progress in the determination of genetic causes of APA. The use of next-generation sequencing (NGS) has led to the identification of somatic mutations in APA that cause excess aldosterone production. Most of the affected genes encode ion channels or transporters. Somatic activating mutations in CTNNB1 (β;-catenin) have also been detected in 2–5% of APA. As a possible pathogenesis, an association of CTNNB1-mutated APA with pregnancy and menopause has been proposed. A recent study reported double somatic mutations in CTNNB1 and GNA11/Q in APA. However, due to its rare incidence, characteristics of APA with these mutations are not well determined. Herein, we report a case of APA harboring somatic CTNNB1 and GNA11 mutations. Case presentation: A 46-year-old Japanese woman presented with hypertension and spontaneous hypokalemia. She had no history of pregnancy-induced hypertension. She had regular menstrual cycle at presentation. Endocrine testing showed elevated plasma aldosterone concentration (677.5 pg/mL) under suppressed renin (plasma renin activity, 0.3 ng/mL/h). Computed tomography revealed a 2 cm right adrenal mass. Adrenal venous sampling indicated excess aldosterone production from the right adrenal gland. NP-59 scintigraphy further demonstrated increased tracer uptake in the right adrenal lesion. She underwent right laparoscopic adrenalectomy. Histologic diagnosis of the resected tumor was adrenocortical adenoma based on the Weiss criteria. Notably, Ki-67 labeling index was high (6% at hotspots). After surgery, her blood pressure and serum potassium both normalized. Based on the PASO (the primary aldosteronism surgical outcome) study criteria, PA remained clinically and biochemically cured at follow-up 18 months after surgery. Methods: Formalin-fixed, paraffin-embedded adrenal tumor tissue was used for immunohistochemical and genetic analysis. Results: Immunohistochemistry (IHC) showed high and diffuse expression of CYP11B2 (aldosterone synthase) within the tumor, whereas 11β;-hydroxylase (CYP11B1, a steroidogenic enzyme for cortisol biosynthesis) was mostly negative. VSNL1, a marker for the zona glomerulosa where physiologic aldosterone biosynthesis occurs, was highly expressed within the tumor. CYP11B2 IHC-guided targeted NGS identified concurrent somatic CTNNB1 (p.D32Y) and GNA11 (p.Q209H) mutations with similar variant allele frequencies (29.5% and 29.7%, respectively). Conclusions: To best of our knowledge, this is the first Asian case of APA with CTNNB1 and GNA11 mutations. Detailed clinical and histologic examination would provide useful information for better characterization of patients with PA due to these rare mutations.