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

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.

• Authors: Tobias Åkerström, Holger Sven Willenberg, Kenko Cupisti, Julian Ip, Samuel Backman, Ana Moser, Rajani Maharjan, Bruce Robinson, K Alexander Iwen, Henning Dralle, Cristina D Volpe, Martin Bäckdahl, Johan Botling, Peter Stålberg, Gunnar Westin, Martin K Walz, Hendrik Lehnert, Stan Sidhu, Jan Zedenius, Peyman Björklund, Per Hellman
• Journal: Endocrine-related cancer (Endocr Relat Cancer) Vol. 22 Issue 5 Pg. 735-44 (Oct 2015) ISSN: 1479-6821 [Electronic] England
• PMID: 26285814 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 Society for Endocrinology.

Chemical References

• Biomarkers, Tumor
• CACNA1D protein, human
• Calcium Channels, L-Type
• Aldosterone
• ATP1A1 protein, human
• Plasma Membrane Calcium-Transporting ATPases
• ATP2B3 protein, human
• Sodium-Potassium-Exchanging ATPase

Topics

• Adrenal Cortex Neoplasms (genetics, metabolism, pathology)
• Adrenocortical Adenoma (genetics, metabolism, pathology)
• Adult
• Aged
• Aged, 80 and over
• Aldosterone (metabolism)
• Biomarkers, Tumor (genetics)
• Calcium Channels, L-Type (genetics)
• Female
• Follow-Up Studies
• Gene Expression Profiling
• Humans
• Hyperaldosteronism (genetics, metabolism, pathology)
• Immunoenzyme Techniques
• Male
• Middle Aged
• Mutation
• Neoplasm Staging
• Phenotype
• Plasma Membrane Calcium-Transporting ATPases (genetics)
• Polymerase Chain Reaction
• Prognosis
• Sodium-Potassium-Exchanging ATPase (genetics)