We did, however, find gene body hypermethylation in CDH7, a type 2 classical cadherin from the cadherin superfamily, when comparing noninvasive to invasive NFAs. Further validation in a larger PA sample population is nevertheless warranted to identify and confirm genomic and epigenomic pathways involved in tumor invasion. Meanwhile, other epigenetic mechanisms should be explored in an effort to explain the character of PA invasion and prioritize genes associated with this clinically significant phenotype. The anterior pituitary gland secretes six known hormones that regulate homeostasis, including adrenocorticotropic hormone, growth hormone, prolactin, thyroid-stimulating hormone, follicle-stimulating hormone and luteinizing hormone. Clinically nonfunctioning PAs are not able to synthesize and/or secrete functional hormones, although in a majority of cases they nevertheless demonstrate positive immunostaining for LH, FSH, and/or the alpha-subunit. PAs are monoclonal in origin and typically benign tumors, suggesting they arise from expansion of single precursor cells that possess a unique proliferative advantage. These monoclonal adenomas therefore secrete specific hormones reflective of their differentiated cell of origin. In the current study, hierarchical clustering analysis readily separated somatotroph adenomas from nonfunctional adenomas, suggesting a potential role of DNA methylation in the differentiation and/or functional regulation of these tumors. Furthermore, an unexpected and interesting finding in the current study was that the functional corticotroph adenoma causing Cushing’s disease and the silent corticotroph adenoma clustered to the same hierarchical group. The exact mechanisms by which nonfunctioning PAs retain immunostaining but fail to produce clinically-active hormones remains to be determined. Our genome-scale screening of variability in DNA methylation between functional and nonfunctional PAs suggests that nonfunctional PAs are globally hypermethylated compared to functional ones. This finding is particularly interesting in that the most differentially methylated gene, KCNAB2, encodes a potassium ion-channel that has been previously implicated in endocrine function pertaining to insulin secretion. Pituitary cells resemble neurons and muscle fibers in that they also fire action potentials, which are mediated via expression of numerous voltage-gated sodium, potassium, calcium and chloride channels. These APs are accompanied by a rise in intracellular calcium and spontaneous electrical activity that drives intracellular calcium concentrations above the threshold for stimulus-secretion and stimulus-transcription coupling. KCNAB2 is a subunit of the shaker-related voltage dependent potassium channel, and upon binding to K + channel alpha subunits, contributes to regulation of channel excitability. In addition, KCNAB2 has been demonstrated as an functional aldoketoreductase.