Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks

Kazutaka Nanba¹, Kei Omata², Celso E Gomez-Sanchez^{3

4}, Constantine A Stratakis⁵, Andrew P Demidowich⁵, Mari Suzuki⁵, Lester D R Thompson⁶, Debbie L Cohen⁷, James M Luther⁸, Lan Gellert⁹, Anand Vaidya¹⁰, Justine A Barletta¹¹, Tobias Else¹², Thomas J Giordano^{2

12

13}, Scott A Tomlins^{2

13

14

15}, William E Rainey^{1

12}

Affiliations

¹ From the Department of Molecular and Integrative Physiology (K.N., W.E.R.), University of Michigan, Ann Arbor.
² Department of Pathology (K.O., T.J.G., S.A.T.), University of Michigan, Ann Arbor.
³ Endocrine and Research Service, G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS (C.E.G.-S.).
⁴ Division of Endocrinology, University of Mississippi Medical Center, Jackson (C.E.G.-S.).
⁵ Section of Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S., A.P.D., M.S.).
⁶ Department of Pathology, Woodland Hills Medical Center, Southern California Permanente Medical Group (L.D.R.T.).
⁷ Renal, Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.L.C.).
⁸ Division of Clinical Pharmacology (J.M.L.), Vanderbilt University Medical Center, Nashville, TN.
⁹ Department of Pathology, Microbiology and Immunology (L.G.), Vanderbilt University Medical Center, Nashville, TN.
¹⁰ Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension (A.V.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
¹¹ Department of Pathology (J.A.B.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
¹² Division of Metabolism, Endocrine, and Diabetes, Department of Internal Medicine (T.E., T.J.G., W.E.R.), University of Michigan, Ann Arbor.
¹³ Rogel Cancer Center (T.J.G., S.A.T.), University of Michigan, Ann Arbor.
¹⁴ Department of Urology (S.A.T.), University of Michigan, Ann Arbor.
¹⁵ Michigan Center for Translational Pathology (S.A.T.), University of Michigan, Ann Arbor.

PMID: 30739536
PMCID: PMC6416065
DOI: 10.1161/HYPERTENSIONAHA.118.12070

Multicenter Study

Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks

Kazutaka Nanba et al. Hypertension. 2019 Apr.

. 2019 Apr;73(4):885-892.

doi: 10.1161/HYPERTENSIONAHA.118.12070.

Authors

Affiliations

¹ From the Department of Molecular and Integrative Physiology (K.N., W.E.R.), University of Michigan, Ann Arbor.
² Department of Pathology (K.O., T.J.G., S.A.T.), University of Michigan, Ann Arbor.
³ Endocrine and Research Service, G.V. (Sonny) Montgomery VA Medical Center, Jackson, MS (C.E.G.-S.).
⁴ Division of Endocrinology, University of Mississippi Medical Center, Jackson (C.E.G.-S.).
⁵ Section of Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD (C.A.S., A.P.D., M.S.).
⁶ Department of Pathology, Woodland Hills Medical Center, Southern California Permanente Medical Group (L.D.R.T.).
⁷ Renal, Electrolyte and Hypertension Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia (D.L.C.).
⁸ Division of Clinical Pharmacology (J.M.L.), Vanderbilt University Medical Center, Nashville, TN.
⁹ Department of Pathology, Microbiology and Immunology (L.G.), Vanderbilt University Medical Center, Nashville, TN.
¹⁰ Center for Adrenal Disorders, Division of Endocrinology, Diabetes, and Hypertension (A.V.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
¹¹ Department of Pathology (J.A.B.), Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
¹² Division of Metabolism, Endocrine, and Diabetes, Department of Internal Medicine (T.E., T.J.G., W.E.R.), University of Michigan, Ann Arbor.
¹³ Rogel Cancer Center (T.J.G., S.A.T.), University of Michigan, Ann Arbor.
¹⁴ Department of Urology (S.A.T.), University of Michigan, Ann Arbor.
¹⁵ Michigan Center for Translational Pathology (S.A.T.), University of Michigan, Ann Arbor.

PMID: 30739536
PMCID: PMC6416065
DOI: 10.1161/HYPERTENSIONAHA.118.12070

Abstract

Somatic mutations have been identified in aldosterone-producing adenomas (APAs) in genes that include KCNJ5, ATP1A1, ATP2B3, and CACNA1D. Based on independent studies, there appears to be racial differences in the prevalence of somatic KCNJ5 mutations, particularly between East Asians and Europeans. Despite the high cardiovascular disease mortality of blacks, there have been no studies focusing on somatic mutations in APAs in this population. In the present study, we investigated genetic characteristics of APAs in blacks using a CYP11B2 (aldosterone synthase) immunohistochemistry-guided next-generation sequencing approach. The adrenal glands with adrenocortical adenomas from 79 black patients with primary aldosteronism were studied. Seventy-three tumors from 69 adrenal glands were confirmed to be APAs by CYP11B2 immunohistochemistry. Sixty-five of 73 APAs (89%) had somatic mutations in aldosterone-driver genes. Somatic CACNA1D mutations were the most prevalent genetic alteration (42%), followed by KCNJ5 (34%), ATP1A1 (8%), and ATP2B3 mutations (4%). CACNA1D mutations were more often observed in APAs from males than those from females (55% versus 29%, P=0.033), whereas KCNJ5 mutations were more prevalent in APAs from females compared with those from males (57% versus 13%, P<0.001). No somatic mutations in aldosterone-driver genes were identified in tumors without CYP11B2 expression. In conclusion, 89% of APAs in blacks harbor aldosterone-driving mutations, and unlike Europeans and East Asians, the most frequently mutated aldosterone-driver gene was CACNA1D. Determination of racial differences in the prevalence of aldosterone-driver gene mutations may facilitate the development of personalized medicines for patients with primary aldosteronism.

Keywords: adrenal glands; adrenocortical adenoma; aldosterone; hyperaldosteronism; mutation.

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Figures

**Figure 1.. Study design based on the results of CYP11B2 immunohistochemistry**
CYP11B2-expressing tumors were considered as aldosterone-producing adenomas (APAs) by CYP11B2 immunohistochemistry (IHC). *Four adrenals had two independent APAs within the same adrenal; †Ten CYP11B2-negative tumors adjacent to APAs were also assessed. FFPE, formalin-fixed paraffin-embedded.

**Figure 2.. Histopathologic findings of multiple APAs and a CYP11B2-negative adrenocortical adenoma within the same adrenal gland**
A and B. Scanned images of adrenal gland and tumors following CYP11B2 IHC (brown, CYP11B2). Two FFPE blocks were used for examination (A, block 1; B, block 2). Scale bar, 5 mm. **C-E.** High magnification view of each tumor (C, APA1; D, APA2; E, T1). APA1 is mostly composed of lipid-rich clear cells with moderate expression of CYP11B1 as well as high CYP11B2, whereas APA2 is mainly composed of lipid-poor compact cells with intense CYP11B2 expression. Scale bar, 100 μm. H&E, hematoxylin and eosin staining; APA, aldosterone-producing adenoma; T1, CYP11B2-negative tumor.

**Figure 3.. Histopathologic findings of multple aldosterone-producing cell clusters and a CYP11B2-negative adrenocortical adenoma**
A and B. Scanned images of adrenal gland following IHC for CYP11B2 (A) and CYP11B1 (B); Scale bar, 5 mm. **C-E.** Higher magnification view of APCC1 (C), APCC 2 (D), and the CYP11B2-negative tumor (T1; E). Scale bar, 100 μm. H&E, hematoxylin and eosin staining; APCC, aldosterone-producing cell cluster.

See this image and copyright information in PMC

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Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks

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Genetic Characteristics of Aldosterone-Producing Adenomas in Blacks

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