Abstract
Pituitary adenomas (PAs) are neoplasms that may cause a variety of neurological and endocrine effects. Although known causal contributors include heredity, hormonal influence and somatic mutations, the pathophysiologic mechanisms driving tumorigenesis and invasion of sporadic PAs remain unknown. We hypothesized that alterations in DNA methylation are associated with PA invasion and histopathology subtype, and that genome-scale methylation analysis may complement current classification methods for sporadic PAs. Twenty-four surgically-resected sporadic PAs with varying histopathological subtypes were assigned dichotomized Knosp invasion scores and examined using genome-wide DNA methylation profiling and RNA sequencing. PA samples clustered into subgroups according to functional status. Compared with hormonally-active PAs, nonfunctional PAs exhibited global DNA hypermethylation (mean beta-value 0.47 versus 0.42, P = 0.005); the most significant site of differential DNA methylation was within the promoter region of the potassium voltage-gated channel KCNAB2 (FDR = 5.11×10−10). Pathway analysis of promoter-associated CpGs showed that nonfunctional PAs are potentially associated with the ion-channel activity signal pathway. DNA hypermethylation tended to be negatively correlated with gene expression. DNA methylation analysis may be used to identify candidate genes involved in PA function and may potentially complement current standard immunostaining classification in sporadic PAs. DNA hypermethylation of KCNAB2 and downstream ion-channel activity signal pathways may contribute to the endocrine-inactive status of nonfunctional PAs.
Highlights
Pituitary adenomas (PAs) are typically benign monoclonal neoplasms with an overall prevalence of 16.7% (14.4% in autopsy studies and 22.5% in imaging studies) in the general population
Genome-scale DNA methylation screening of PAs was performed to investigate whether DNA methylation was associated with PA invasion and histopathological subtype classification
This is the first genome-scale DNA methylation analysis of sporadic PAs, demonstrating that epigenetic modification of key gene substrates may in part account for functional differentiation of PAs, and that DNA methylation analysis of key candidate genes may potentially be used to complement PA current histopathology subtype classification systems
Summary
Pituitary adenomas (PAs) are typically benign monoclonal neoplasms with an overall prevalence of 16.7% (14.4% in autopsy studies and 22.5% in imaging studies) in the general population. Invasion into surrounding anatomical structures (e.g. cavernous sinus invasion) remains a major barrier to achieving long-term tumor and disease control, especially in cases of functional PAs resulting in malignant endocrinopathies such as Cushing’s disease or acromegaly [3]. In sporadic PAs, it has been suggested that alterations in epigenetic regulation, and DNA methylation, may play a prominent role in PA tumorigenesis and invasion, likely via loss or reduced expression of tumor suppressor genes (TSGs) [6]. Other studies have shown that tumor specific epigenetic silencing of cadherin 13, H-cadherin (CDH13) and cadherin 1, type, E-cadherin (CDH1), alone or in combination, were involved in PA development and invasion [11], and CpG hypermethylation-mediated glutathione S-transferase pi gene (GSTP1) inactivation was a common finding in PAs potentially contributing to their invasive behavior [12]. Few prior studies have utilized genome-scale approaches according to functional PA subtypes and phenotypical invasion status to identify candidate genes involved in these processes [13,14]
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