Aldosterone-Producing Adenomas

Histopathology-Genotype Correlation and Identification of a Novel CACNA1D Mutation

Geok Chin Tan, Giulia Negro, Alexandra Pinggera, Nur Maya Sabrina Tizen Laim, Isa Mohamed Rose, Jiri Ceral, Ales Ryska, Long Kha Chin, Nor Azmi Kamaruddin, Norfilza Mohd Mokhtar, A. Rahman A. Jamal, Norlela Sukor, Miroslav Solar, Joerg Striessnig, Morris Jonathan Brown, Azizan Elena Aisha

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel's inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20×10-4). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%-1.9%] versus 0.4% [0.3%-0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype.

Original languageEnglish
Pages (from-to)129-136
Number of pages8
JournalHypertension
Volume70
Issue number1
DOIs
Publication statusPublished - 1 Jul 2017

Fingerprint

Aldosterone
Adenoma
Genotype
Mutation
Zona Fasciculata
Staining and Labeling
Cytochrome P-450 CYP11B2
Hyperaldosteronism
Exons

Keywords

  • adrenal
  • aldosterone
  • primary hyperaldosteronism
  • zona fasciculata
  • zona glomerulosa

ASJC Scopus subject areas

  • Internal Medicine

Cite this

Aldosterone-Producing Adenomas : Histopathology-Genotype Correlation and Identification of a Novel CACNA1D Mutation. / Tan, Geok Chin; Negro, Giulia; Pinggera, Alexandra; Laim, Nur Maya Sabrina Tizen; Rose, Isa Mohamed; Ceral, Jiri; Ryska, Ales; Chin, Long Kha; Kamaruddin, Nor Azmi; Mohd Mokhtar, Norfilza; A. Jamal, A. Rahman; Sukor, Norlela; Solar, Miroslav; Striessnig, Joerg; Brown, Morris Jonathan; Elena Aisha, Azizan.

In: Hypertension, Vol. 70, No. 1, 01.07.2017, p. 129-136.

Research output: Contribution to journalArticle

Tan, Geok Chin ; Negro, Giulia ; Pinggera, Alexandra ; Laim, Nur Maya Sabrina Tizen ; Rose, Isa Mohamed ; Ceral, Jiri ; Ryska, Ales ; Chin, Long Kha ; Kamaruddin, Nor Azmi ; Mohd Mokhtar, Norfilza ; A. Jamal, A. Rahman ; Sukor, Norlela ; Solar, Miroslav ; Striessnig, Joerg ; Brown, Morris Jonathan ; Elena Aisha, Azizan. / Aldosterone-Producing Adenomas : Histopathology-Genotype Correlation and Identification of a Novel CACNA1D Mutation. In: Hypertension. 2017 ; Vol. 70, No. 1. pp. 129-136.
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abstract = "Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7{\%}), 7 adenomas had an ATP1A1 mutation (25{\%}), and 4 adenomas had a CACNA1D mutation (14.3{\%}). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel's inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20×10-4). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7{\%} [0.5{\%}-1.9{\%}] versus 0.4{\%} [0.3{\%}-0.7{\%}]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30{\%} nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype.",
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T2 - Histopathology-Genotype Correlation and Identification of a Novel CACNA1D Mutation

AU - Tan, Geok Chin

AU - Negro, Giulia

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AU - Laim, Nur Maya Sabrina Tizen

AU - Rose, Isa Mohamed

AU - Ceral, Jiri

AU - Ryska, Ales

AU - Chin, Long Kha

AU - Kamaruddin, Nor Azmi

AU - Mohd Mokhtar, Norfilza

AU - A. Jamal, A. Rahman

AU - Sukor, Norlela

AU - Solar, Miroslav

AU - Striessnig, Joerg

AU - Brown, Morris Jonathan

AU - Elena Aisha, Azizan

PY - 2017/7/1

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N2 - Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel's inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20×10-4). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%-1.9%] versus 0.4% [0.3%-0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype.

AB - Mutations in KCNJ5, ATP1A1, ATP2B3, CACNA1D, and CTNNB1 are thought to cause the excessive autonomous aldosterone secretion of aldosterone-producing adenomas (APAs). The histopathology of KCNJ5 mutant APAs, the most common and largest, has been thoroughly investigated and shown to have a zona fasciculata-like composition. This study aims to characterize the histopathologic spectrum of the other genotypes and document the proliferation rate of the different sized APAs. Adrenals from 39 primary aldosteronism patients were immunohistochemically stained for CYP11B2 to confirm diagnosis of an APA. Twenty-eight adenomas had sufficient material for further analysis and were target sequenced at hot spots in the 5 causal genes. Ten adenomas had a KCNJ5 mutation (35.7%), 7 adenomas had an ATP1A1 mutation (25%), and 4 adenomas had a CACNA1D mutation (14.3%). One novel mutation in exon 28 of CACNA1D (V1153G) was identified. The mutation caused a hyperpolarizing shift of the voltage-dependent activation and inactivation and slowed the channel's inactivation kinetics. Immunohistochemical stainings of CYP17A1 as a zona fasciculata cell marker and Ki67 as a proliferation marker were used. KCNJ5 mutant adenomas showed a strong expression of CYP17A1, whereas ATP1A1/CACNA1D mutant adenomas had a predominantly negative expression (P value =1.20×10-4). ATP1A1/CACNA1D mutant adenomas had twice the nuclei with intense staining of Ki67 than KCNJ5 mutant adenomas (0.7% [0.5%-1.9%] versus 0.4% [0.3%-0.7%]; P value =0.04). Further, 3 adenomas with either an ATP1A1 mutation or a CACNA1D mutation had >30% nuclei with moderate Ki67 staining. In summary, similar to KCNJ5 mutant APAs, ATP1A1 and CACNA1D mutant adenomas have a seemingly specific histopathologic phenotype.

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