TY - JOUR
T1 - Genetic characteristics of aldosterone-producing adenomas in blacks
AU - Nanba, Kazutaka
AU - Omata, Kei
AU - Gomez-Sanchez, Celso E.
AU - Stratakis, Constantine A.
AU - Demidowich, Andrew P.
AU - Suzuki, Mari
AU - Thompson, Lester D.R.
AU - Cohen, Debbie L.
AU - Luther, James M.
AU - Gellert, Lan
AU - Vaidya, Anand
AU - Barletta, Justine A.
AU - Else, Tobias
AU - Giordano, Thomas J.
AU - Tomlins, Scott A.
AU - Rainey, William E.
N1 - Funding Information:
This work was supported by grants from American Heart Association (17SDG33660447 to K. Nanba and 14SDG17990000 to T. Else), National Institute of Diabetes and Digestive and Kidney Diseases (DK106618 to W.E. Rainey and S.A. Tomlins, DK096994 to J.M. Luther, and DK115392 to A. Vaidya), and National Heart, Lung, and Blood Institute (HL027255 to C.E. Gomez-Sanchez and HL130106 to T. Else). C.E. Gomez-Sanchez was also supported by the National Institute of General Medical Sciences grant U54 GM115428. S.A. Tomlins was supported by the A. Alfred Taubman Medical Research Institute and a National Cancer Institute Grant CA46592 (to the Michigan Cancer Center Core). Finally, this work was in part supported by a Bench-to-Bedside Award (B7BA) by the National Institutes of Health Clinical Center to C.A. Stratakis and W.E. Rainey, and the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institute of Health that funds Dr Stratakis’ laboratory.
Funding Information:
We thank Michelle Vinco and Farah Keyoumarsi at the University of Michigan for assistance in case identification and slide preparation and Amy R. Blinder at the University of Michigan for technical assistance. We also thank David Madrigal and Sarah Brand at the University of Michigan for their organizational role in the American-Australian-Asian Adrenal Alliance (A5) study group. We acknowledge the Vanderbilt Translational Pathology Shared Resource for its assistance in research histology (supported by National Cancer Institute/National Institutes of Health Cancer Center Support Grant 5P30 CA68485-19). Finally, we thank Drs Charalampos Lyssikatos, Elena Belyavskaya, and Fabio Faucz at National Institute of Child Health and Human Development, National Institute of Health for their role in collecting and shipping tissues for this study.
Publisher Copyright:
© 2019 American Heart Association, Inc.
PY - 2019/4/1
Y1 - 2019/4/1
N2 - 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.
AB - 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.
KW - Adrenal glands
KW - Adrenocortical adenoma
KW - Aldosterone
KW - Hyperaldosteronism
KW - Mutation
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U2 - 10.1161/HYPERTENSIONAHA.118.12070
DO - 10.1161/HYPERTENSIONAHA.118.12070
M3 - Article
C2 - 30739536
AN - SCOPUS:85062864736
VL - 73
SP - 885
EP - 892
JO - Hypertension
JF - Hypertension
SN - 0194-911X
IS - 4
ER -