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Endocr Relat Cancer. 2015 Oct;22(5):735-44. doi: 10.1530/ERC-15-0321.

Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas.

Author information

1
Department of Surgical SciencesUppsala University, Uppsala, SwedenDepartment of Endocrinology and MetabolismRostock University Medical Center, GermanyGeneralVisceral and Pediatric Surgery University Hospital Düsseldorf, Düsseldorf, GermanyUniversity of SydneyEndocrine Surgical Unit and Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, AustraliaDepartment of Medicine IUniversity of Lübeck, University Hospital, Lübeck, GermanyDepartment of GeneralVisceral and Vascular Surgery, University Hospital, University of Halle-Wittenberg, Halle/Saale, GermanyDepartment of Molecular Medicine and SurgeryEndocrine Surgery Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDepartment of ImmunologyGenetics and Pathology, Uppsala University, Uppsala, SwedenKlinik für Chirurgie und Zentrum für Minimal Invasive ChirurgieKliniken Essen-Mitte, Essen, Germany tobias.akerstrom@surgsci.uu.se.
2
Department of Surgical SciencesUppsala University, Uppsala, SwedenDepartment of Endocrinology and MetabolismRostock University Medical Center, GermanyGeneralVisceral and Pediatric Surgery University Hospital Düsseldorf, Düsseldorf, GermanyUniversity of SydneyEndocrine Surgical Unit and Cancer Genetics, Hormones and Cancer Group, Kolling Institute of Medical Research, Royal North Shore Hospital, Sydney, AustraliaDepartment of Medicine IUniversity of Lübeck, University Hospital, Lübeck, GermanyDepartment of GeneralVisceral and Vascular Surgery, University Hospital, University of Halle-Wittenberg, Halle/Saale, GermanyDepartment of Molecular Medicine and SurgeryEndocrine Surgery Unit, Karolinska Institutet, Karolinska University Hospital, Stockholm, SwedenDepartment of ImmunologyGenetics and Pathology, Uppsala University, Uppsala, SwedenKlinik für Chirurgie und Zentrum für Minimal Invasive ChirurgieKliniken Essen-Mitte, Essen, Germany.

Abstract

Aldosterone-producing adenomas (APAs) are found in 1.5-3.0% of hypertensive patients in primary care and can be cured by surgery. Elucidation of genetic events may improve our understanding of these tumors and ultimately improve patient care. Approximately 40% of APAs harbor a missense mutation in the KCNJ5 gene. More recently, somatic mutations in CACNA1D, ATP1A1 and ATP2B3, also important for membrane potential/intracellular Ca(2) (+) regulation, were observed in APAs. In this study, we analyzed 165 APAs for mutations in selected regions of these genes. We then correlated mutational findings with clinical and molecular phenotype using transcriptome analysis, immunohistochemistry and semiquantitative PCR. Somatic mutations in CACNA1D in 3.0% (one novel mutation), ATP1A1 in 6.1% (six novel mutations) and ATP2B3 in 3.0% (two novel mutations) were detected. All observed mutations were located in previously described hotspot regions. Patients with tumors harboring mutations in CACNA1D, ATP1A1 and ATP2B3 were operated at an older age, were more often male and had tumors that were smaller than those in patients with KCNJ5 mutated tumors. Microarray transcriptome analysis segregated KCNJ5 mutated tumors from ATP1A1/ATP2B3 mutated tumors and those without mutation. We observed significant transcription upregulation of CYP11B2, as well as the previously described glomerulosa-specific gene NPNT, in ATP1A1/ATP2B3 mutated tumors compared to KCNJ5 mutated tumors. In summary, we describe novel somatic mutations in proteins regulating the membrane potential/intracellular Ca(2) (+) levels, and also a distinct mRNA and clinical signature, dependent on genetic alteration.

KEYWORDS:

ATP1A1; CACNA1D; KCNJ5; aldosterone-producing adenoma; primary aldosteronism

PMID:
26285814
DOI:
10.1530/ERC-15-0321
[Indexed for MEDLINE]

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