Kazutaka Nanba1, Andrew X Chen1, Kei Omata1, Michelle Vinco1, Thomas J Giordano1, Tobias Else1, Gary D Hammer1, Scott A Tomlins1, William E Rainey1. 1. Departments of Molecular and Integrative Physiology and Internal Medicine (K.N., A.X.C., G.D.H., W.E.R.), Pathology (K.O., M.V., T.J.G., S.A.T.), and Urology (S.A.T.), Comprehensive Cancer Center (T.J.G., T.E., S.A.T.), Division of Metabolism, Endocrinology, and Diabetes (T.J.G., T.E., G.D.H.), Endocrine Oncology Program (T.E., G.D.H.), Center for Organogenesis, and Michigan Center for Translational Pathology (S.A.T.), University of Michigan, Ann Arbor, Michigan 48109.
Abstract
CONTEXT: The use of next-generation sequencing has resulted in the identification of recurrent somatic mutations underlying primary aldosteronism (PA). However, significant gaps remain in our understanding of the relationship between tumor aldosterone synthase (CYP11B2) expression and somatic mutation status. OBJECTIVE: The objective of the study was to investigate tumor CYP11B2 expression and somatic aldosterone-driver gene mutation heterogeneity. METHODS: Fifty-one adrenals from 51 PA patients were studied. Immunohistochemistry for CYP11B2 was performed. Aldosterone-producing adenomas with intratumor CYP11B2 heterogeneity were analyzed for mutation status using targeted next-generation sequencing. DNA was isolated from CYP11B2-positive, CYP11B2-negative, and adjacent normal areas from formalin-fixed, paraffin-embedded sections. RESULTS: Of 51 adrenals, seven (14 %) showed distinct heterogeneity in CYP11B2 by immunohistochemistry, including six adenomas with intratumor heterogeneity and one multinodular hyperplastic adrenal with both CYP11B2-positive and -negative nodules. Of the six adrenocortical adenomas with CYP11B2 heterogeneity, three had aldosterone-regulating mutations (CACNA1D p.F747C, KCNJ5 p.L168R, ATP1A1 p.L104R) only in CYP11B2-positive regions, and one had two different mutations localized to two histologically distinct CYP11B2-positive regions (ATP2B3 p.L424_V425del, KCNJ5 p.G151R). Lastly, one adrenal with multiple CYP11B2-expressing nodules showed different mutations in each (CACNA1D p.F747V and ATP1A1 p.L104R), and no mutations were identified in CYP11B2-negative nodule or adjacent normal adrenal. CONCLUSIONS: Adrenal tumors in patients with PA can demonstrate clear heterogeneity in CYP11B2 expression and somatic mutations in driver genes for aldosterone production. These findings suggest that aldosterone-producing adenoma tumorigenesis can occur within preexisting nodules through the acquisition of somatic mutations that drive aldosterone production.
CONTEXT: The use of next-generation sequencing has resulted in the identification of recurrent somatic mutations underlying primary aldosteronism (PA). However, significant gaps remain in our understanding of the relationship between tumoraldosterone synthase (CYP11B2) expression and somatic mutation status. OBJECTIVE: The objective of the study was to investigate tumorCYP11B2 expression and somatic aldosterone-driver gene mutation heterogeneity. METHODS: Fifty-one adrenals from 51 PA patients were studied. Immunohistochemistry for CYP11B2 was performed. Aldosterone-producing adenomas with intratumor CYP11B2 heterogeneity were analyzed for mutation status using targeted next-generation sequencing. DNA was isolated from CYP11B2-positive, CYP11B2-negative, and adjacent normal areas from formalin-fixed, paraffin-embedded sections. RESULTS: Of 51 adrenals, seven (14 %) showed distinct heterogeneity in CYP11B2 by immunohistochemistry, including six adenomas with intratumor heterogeneity and one multinodular hyperplastic adrenal with both CYP11B2-positive and -negative nodules. Of the six adrenocortical adenomas with CYP11B2 heterogeneity, three had aldosterone-regulating mutations (CACNA1Dp.F747C, KCNJ5p.L168R, ATP1A1p.L104R) only in CYP11B2-positive regions, and one had two different mutations localized to two histologically distinct CYP11B2-positive regions (ATP2B3p.L424_V425del, KCNJ5p.G151R). Lastly, one adrenal with multiple CYP11B2-expressing nodules showed different mutations in each (CACNA1Dp.F747V and ATP1A1p.L104R), and no mutations were identified in CYP11B2-negative nodule or adjacent normal adrenal. CONCLUSIONS:Adrenal tumors in patients with PA can demonstrate clear heterogeneity in CYP11B2 expression and somatic mutations in driver genes for aldosterone production. These findings suggest that aldosterone-producing adenoma tumorigenesis can occur within preexisting nodules through the acquisition of somatic mutations that drive aldosterone production.
Authors: L S Kirschner; J A Carney; S D Pack; S E Taymans; C Giatzakis; Y S Cho; Y S Cho-Chung; C A Stratakis Journal: Nat Genet Date: 2000-09 Impact factor: 38.330
Authors: Kazutaka Nanba; Amy R Blinder; Juilee Rege; Namita G Hattangady; Tobias Else; Chia-Jen Liu; Scott A Tomlins; Pankaj Vats; Chandan Kumar-Sinha; Thomas J Giordano; William E Rainey Journal: Hypertension Date: 2020-01-27 Impact factor: 10.190
Authors: Kazutaka Nanba; Kei Omata; Celso E Gomez-Sanchez; Constantine A Stratakis; Andrew P Demidowich; Mari Suzuki; Lester D R Thompson; Debbie L Cohen; James M Luther; Lan Gellert; Anand Vaidya; Justine A Barletta; Tobias Else; Thomas J Giordano; Scott A Tomlins; William E Rainey Journal: Hypertension Date: 2019-04 Impact factor: 10.190
Authors: Kazutaka Nanba; Kei Omata; Scott A Tomlins; Thomas J Giordano; Gary D Hammer; William E Rainey; Tobias Else Journal: Eur J Endocrinol Date: 2016-05-10 Impact factor: 6.664
Authors: Teresa M Seccia; Brasilina Caroccia; Elise P Gomez-Sanchez; Paul-Emmanuel Vanderriele; Celso E Gomez-Sanchez; Gian Paolo Rossi Journal: Hypertension Date: 2017-09-25 Impact factor: 10.190
Authors: Aya T Nanba; Kazutaka Nanba; James B Byrd; James J Shields; Thomas J Giordano; Barbara S Miller; William E Rainey; Richard J Auchus; Adina F Turcu Journal: Clin Endocrinol (Oxf) Date: 2017-09-04 Impact factor: 3.478
Authors: Antonio M Lerario; Kazutaka Nanba; Amy R Blinder; Sachiko Suematsu; Masao Omura; Tetsuo Nishikawa; Thomas J Giordano; William E Rainey; Tobias Else Journal: Endocr Relat Cancer Date: 2019-02-01 Impact factor: 5.678
Authors: Kazutaka Nanba; Kei Omata; Tobias Else; Peter C C Beck; Aya T Nanba; Adina F Turcu; Barbra S Miller; Thomas J Giordano; Scott A Tomlins; William E Rainey Journal: J Clin Endocrinol Metab Date: 2018-10-01 Impact factor: 5.958