Genome-wide DNA Methylation Differences in Non-functioning Pituitary Adenomas With and Without Postsurgical Progression

J Clin Endocrinol Metab. 2022 Apr 29;dgac266. doi: 10.1210/clinem/dgac266. Online ahead of print.


Context: Tumor progression in surgically treated patients with non-functioning pituitary adenomas (NFPAs) is associated with excess mortality. Reliable biomarkers allowing early identification of tumor progression are missing.

Objective: To explore DNA methylation patterns associated with tumor progression in NFPA patients.

Design: Case-controlled exploratory trial.

Setting: University Hospital.

Patients: Patients operated for NFPA with immunohistochemical characteristics of a gonadotropinoma were studied. Cases included patients requiring reintervention due to tumor progression (reintervention group, n = 26) and controls who had a post-operative residual tumor without tumor progression for at least 5 years (radiologically stable group, n = 17).

Intervention: None.

Main outcome measure: Genome-wide methylation data from each tumor sample using the Infinium MethylationEPIC BeadChip platform.

Results: The analysis showed that 605 CpG positions were significantly differently methylated (differently methylated positions, DMPs) between the patient groups (false discovery rate adjusted P-value <0.05, beta value >0.2), mapping to 389 genes. The largest number of DMPs were detected in the genes NUP93 and LGALS1. The three hypomethylated DMPs and the three hypermethylated DMPs with the lowest P-values were all significantly (P < 0.05) and individually associated with reintervention-free survival. One of the hypermethylated DMPs with the lowest P-value was located in the gene GABRA1.

Conclusions: In this exploratory study, DNA methylation patterns in NFPA patients were associated with postoperative tumor progression requiring reintervention. The DMPs included genes that have been previously associated with tumor development. Our study is a step towards finding epigenetic signatures to predict tumor progression in patients with NFPA.

Keywords: DNA methylation pattern; non-functioning pituitary adenoma; reintervention; tumor progression.