Purpose Pituitary adenomas (PAs) are one of the most common benign neoplasms of the central nervous system. Although emerging evidence suggests roles for both genetic and epigenetic factors in tumorigenesis, the degree to which these factors contribute to disease remains poorly understood. Experimental Design A multi-platform analysis was performed to identify the genomic and epigenomic underpinnings of disease among the three major subtypes of surgically-resected PAs in 48 patients: growth hormone (GH)-secreting (n=17), adrenocorticotropic hormone (ACTH)-secreting (n=13, including 3 silent-ACTH adenomas), and endocrine-inactive (n=18). Whole-exome sequencing was used to profile the somatic mutational landscape, whole-transcriptome sequencing was used to identify disease specific patterns of gene expression, and array-based DNA methylation profiling was used to examine genome-wide patterns of DNA methylation. Results Recurrent single nucleotide and small indel somatic mutations were infrequent among the three adenoma subtypes. However, somatic copy number alterations (SCNAs) were identified in all three PA subtypes. Methylation analysis revealed adenoma subtype-specific DNA methylation profiles, with GH-secreting adenomas being dominated by hypomethylated sites. Likewise, gene expression patterns revealed adenoma subtype-specific profiles. Integrating DNA methylation and gene expression data revealed that hypomethylation of promoter regions are related with increased expression of GH1 and SSTR5 genes in GH-secreting adenomas and POMCgene in ACTH-secreting adenomas. Finally, multispectral IHC staining of immune-related proteins showed abundant expression of PD-L1among all three adenoma subtypes. Conclusions Taken together, these data stress the contribution of epigenomic alterations to disease specific etiology among adenoma subtypes and highlight potential targets for future immunotherapy-based treatments.
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