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Published on: September 15, 2017
Novel somatic mutations and distinct molecular signature in aldosterone-producing adenomas
Tobias Åkerström1, Holger Sven Willenberg2, Kenko Cupisti2
1Department 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.
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.
Insights
Aldosterone-producing adenomas (APAs) harbor novel somatic mutations in genes regulating cell membrane potential. These genetic alterations correlate with distinct clinical features and gene expression patterns in tumors, offering new insights into APA development.
Area of Science:
- Endocrinology
- Oncology
- Genetics
Background:
- Aldosterone-producing adenomas (APAs) are a common cause of primary aldosteronism, a curable form of hypertension.
- Genetic mutations, particularly in KCNJ5, are known drivers of APA development.
- Understanding the genetic landscape of APAs is crucial for improving diagnosis and patient care.
Purpose of the Study:
- To identify and characterize somatic mutations in CACNA1D, ATP1A1, and ATP2B3 genes within a cohort of 165 APAs.
- To correlate these genetic findings with the clinical and molecular phenotypes of the tumors.
- To investigate potential differences between tumors with mutations in KCNJ5 versus other identified genes.
Main Methods:
- Genomic analysis of 165 APAs for mutations in CACNA1D, ATP1A1, and ATP2B3.
- Clinical data correlation, including patient age, sex, and tumor size.
- Transcriptome analysis (microarray), immunohistochemistry, and semiquantitative PCR to assess molecular phenotypes.
Main Results:
- Novel somatic mutations were identified in CACNA1D (3.0%), ATP1A1 (6.1%), and ATP2B3 (3.0%) within previously described hotspot regions.
- Tumors with CACNA1D, ATP1A1, or ATP2B3 mutations were associated with older patient age, male sex, and smaller tumor size compared to KCNJ5-mutated tumors.
- Transcriptome analysis revealed distinct molecular signatures, with ATP1A1/ATP2B3 mutated tumors showing upregulation of CYP11B2 and NPNT compared to KCNJ5 mutated tumors.
Conclusions:
- This study identifies novel somatic mutations in genes regulating membrane potential and intracellular calcium in APAs.
- Distinct clinical and mRNA expression profiles are associated with different genetic alterations in APAs.
- These findings contribute to a deeper understanding of APA pathogenesis and may inform future therapeutic strategies.
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