ccfDNA analysis for the classification of adrenocortical adenomas

Area of Science:

• Endocrinology
• Oncology
• Molecular Biology

Background:

• Adrenocortical adenomas, including cortisol-producing (CPA), aldosterone-producing (APA), and non-functioning (NFAT) types, frequently harbor somatic alterations.
• Cortisol-producing adenomas manifest as overt Cushing syndrome (CS) or mild autonomous cortisol secretion (MACS).

Purpose of the Study:

• To investigate the detectability of somatic variants in circulating cell-free DNA (ccfDNA) from patients with adrenocortical adenomas.
• To assess the potential utility of ccfDNA analysis in guiding management strategies for these tumors.

Main Methods:

• Blood samples were collected from 44 patients with adrenal adenomas (CPA-MACS, CPA-CS, APA, NFAT) and 23 healthy subjects (HS).
• Circulating cell-free DNA (ccfDNA) and tumor DNA (T-DNA) were extracted and sequenced using a 32-gene panel.
• Leukocyte DNA was used to differentiate somatic from germline variants.

Main Results:

• Patients with adrenal adenomas exhibited significantly higher total ccfDNA concentrations compared to HS, particularly those with CPA-CS.
• Somatic variants were identified in 53% of tumor DNA samples, with mutations found in genes such as PRKACA, CTNNB1, KCNJ5, and CACNA1D.
• No somatic mutations were detected in any of the analyzed ccfDNA samples.

Conclusions:

• Elevated ccfDNA concentrations are associated with cortisol-producing Cushing syndrome (CPA-CS).
• Despite the prevalence of somatic mutations in tumor tissue, current ccfDNA analysis failed to detect these genetic alterations.
• The analyzed ccfDNA approach is currently ineffective for the pre-operative detection of genetic alterations in adrenocortical adenomas.