Article
Deciphering the genetic and epigenetic background of silent and non-silent ACTH adenomas
Entschlüsselung des genetischen und epigenetischen Hintergrunds von stillen und nicht-stillen ACTH-Adenomen
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Published: | June 4, 2021 |
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Objective: Corticotroph adenomas express adrenocorticotrophic hormone (ACTH) and may result in Cushing’s disease (CD) if elevated ACTH blood levels are present. Silent ACTH adenomas (SCA) that express ACTH but do not cause hypercortisolism, might exhibit a more aggressive course and are classified as “aggressive pituitary gland tumors”. Here we show that genetic and epigenetic profiling can distinguish ACTH adenomas from SCA.
Methods: 23 SCA patients and 49 CD patients that underwent transsphenoidal resection were included. Tumor size was measured by MRI. Tumor histology included immunstaining for ACTH and GATA3. Sanger sequencing was performed to analyse mutational burden within the ACTH and USP8 locus. Genome-wide DNA methylation profiling was performed using a 850k and 450k Illumina arrays and classified by the DKFZ brain tumor classifier as well as Prinicipal component (PCA) and copy number variation (CNV) analysis using R (n=36).
Results: Patients with SCA had significantly larger tumors (p< 0.0001). USP8 mutations were only found in CD, while GATA3 expression exclusively appeared in SCA. CNV analysis inferred from the methylation data revealed cytogenetic aberrations across all analyzed samples. tSNE analysis further supported that SCA and CD can be distinguished by their epigenetic profile, also seen in the CNS reference cohort from Capper et al.
Conclusion: SCA show a strong expression of ACTH without causing hypercortisolism. The reason for this is not yet known. Our data suggest that genome-wide DNA methylation profiles allow subgrouping of SCA and CD adenomas that might not be achievable by standard endocrinological testing or histopathology