Prevalence of Somatic Mutations in Aldosterone-Producing Adenomas in Japanese Patients

被引:45
作者
Nanba, Kazutaka [1 ,2 ]
Yamazaki, Yuto [3 ]
Bick, Nolan [4 ]
Onodera, Kei [3 ]
Tezuka, Yuta [5 ,6 ,7 ]
Omata, Kei [5 ,7 ]
Ono, Yoshikiyo [5 ,7 ]
Blinder, Amy R. [1 ]
Tomlins, Scott A. [4 ,8 ,9 ,10 ]
Rainey, William E. [1 ,6 ]
Satoh, Fumitoshi [5 ,7 ]
Sasano, Hironobu [3 ]
机构
[1] Univ Michigan, Dept Mol & Integrat Physiol, Ann Arbor, MI 48109 USA
[2] Natl Hosp Org Kyoto Med Ctr, Dept Endocrinol & Metab, Kyoto 6128555, Japan
[3] Tohoku Univ, Dept Pathol, Grad Sch Med, Sendai, Miyagi 9808575, Japan
[4] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA
[5] Tohoku Univ, Grad Sch Med, Div Nephrol Endocrinol & Vasc Med, Sendai, Miyagi 9808574, Japan
[6] Univ Michigan, Dept Internal Med, Div Metab Endocrinol & Diabet, Ann Arbor, MI 48109 USA
[7] Tohoku Univ, Grad Sch Med, Div Clin Hypertens Endocrinol & Metab, Sendai, Miyagi 9808574, Japan
[8] Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA
[9] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA
[10] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA
关键词
primary aldosteronism; aldosterone-producing adenoma; CYP11B2; somatic mutation; Asian; K+ CHANNEL MUTATIONS; 18-OXOCORTISOL; ATP1A1;
D O I
10.1210/clinem/dgaa595
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Context: Results of previous studies demonstrated clear racial differences in the prevalence of somatic mutations among patients with aldosterone-producing adenoma (APA). For instance, those in East Asian countries have a high prevalence of somatic mutations in KCNJ5, whereas somatic mutations in other aldosterone-driving genes are rare. Objectives: To determine somatic mutation prevalence in Japanese APA patients using an aldosterone synthase (CYP11B2) immunohistochemistry (IHC)-guided sequencing approach. Method: Patients with a unilateral form of primary aldosteronism who underwent adrenalectomy at the Tohoku University Hospital were studied. Based on CYP11B2 immunolocalization of resected adrenals, genomic DNA was isolated from the relevant positive area of 10% formalin-fixed, paraffin-embedded tissue of the APAs. Somatic mutations in aldosterone-driving genes were studied in APAs by direct Sanger sequencing and targeted next-generation sequencing. Results: CYP11B2 IHC-guided sequencing determined APA-related somatic mutations in 102 out of 106 APAs (96%). Somatic KCNJ5 mutation was the most frequent genetic alteration (73%) in this cohort of Japanese patients. Somatic mutations in other aldosterone-driving genes were also identified: CACNA1D (14%), ATP1A1 (5%), ATP2B3 (4%), and CACNA1H (1%), including 2 previously unreported mutations. KCNJ5 mutations were more often detected in APAs from female patients compared with those from male patients [95% (36/38) vs 60% (41/68); P<0.0001]. Conclusion: IHC-guided sequencing defined somatic mutations in over 95% of Japanese APAs. While the dominance of KCNJ5 mutations in this particular cohort was confirmed, a significantly higher KCNJ5 prevalence was detected in female patients. This study provides a better understanding of genetic spectrum of Japanese APA patients.
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页码:1 / 8
页数:8
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