ccfDNA analysis for the classification of adrenocortical adenomas
Xu, Mengjie Tourigny, David S Lippert, Juliane Crastin, Ana Appenzeller, Silke Asia, Miriam Podstawka, Oskar Smith, Gabrielle Elhassan, Yasir S Skordilis, Kassiani
Xu, Mengjie
Tourigny, David S
Lippert, Juliane
Crastin, Ana
Appenzeller, Silke
Asia, Miriam
Podstawka, Oskar
Smith, Gabrielle
Elhassan, Yasir S
Skordilis, Kassiani
Affiliation
University of Birmingham; Taihe Hospital; Hubei University of Medicine; University of Wuerzburg; University Hospital Wuerzburg; University Hospitals Birmingham NHS Foundation Trust
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Publication date
2025-02-01
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Abstract
Background: Somatic alterations are commonly observed in adrenocortical adenomas including cortisol-producing (CPA) [overt Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS)], aldosterone-producing (APA), and non-functioning (NFAT) tumors. We tested whether somatic variants could be detected in circulating cell-free DNA (ccfDNA) from patients with adenomas and potentially contribute to management strategies.
Materials and methods: We investigated 44 patients (17 CPA-MACS, 9 CPA-CS, 12 APA, and 6 NFAT). 23 healthy subjects (HS) served as controls. ccfDNA was extracted from blood samples and quantified with fluorimeter. Tumor DNA (T-DNA) was isolated from paraffin embedded tissue in 17/44 cases. Matched ccfDNA/T-DNA were sequenced using a customized panel including 32 genes. Leucocyte DNA was used to filter out germline variants.
Results: Patients with adenomas had higher total ccfDNA concentrations than HS [median 0.12 (IQR 0.05-0.19) vs. 0.05 (0.00-0.08) ng/µl, P < 0.001], with CPA-CS showing the highest ccfDNA levels [0.18 (0.05-0.47) ng/µl]. Within T-DNA, somatic variants were identified in 53% of adenomas: PRKACA in 2/7 CPA-CS, CTNNB1 in 3/5 CPA-MACS and 1/7 CPA-CS, KCNJ5 in 2/5 APA and CACNA1D in 1/5 APA. Somatic mutations were not detected in any of the investigated ccfDNA samples.
Conclusions: Total ccfDNA concentrations are higher in patients with CPA-CS. Despite the presence of somatic variants in half of tumor samples, we did not detect any at ccfDNA level. Therefore, this approach appears ineffective for pre-operative detection of genetic alterations.
Citation
Xu M, Tourigny DS, Lippert J, Crastin A, Appenzeller S, Asia M, Podstawka O, Smith G, Elhassan YS, Skordilis K, Prete A, Ronchi CL. ccfDNA analysis for the classification of adrenocortical adenomas. J Endocrinol Invest. 2025 May;48(5):1207-1216. doi: 10.1007/s40618-025-02540-5. Epub 2025 Feb 1.
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Article