The Epigenomics of Pituitary Adenoma

Abstract

Background: The vast majority of pituitary tumors are benign and behave accordingly; however, a fraction are invasive and are more aggressive, with a very small fraction being frankly malignant. The cellular pathways that drive transformation in pituitary neoplasms are poorly characterized, and current classification methods are not reliable correlates of clinical behavior. Novel techniques in epigenetics, the study of alterations in gene expression without changes to the genetic code, provide a new dimension to characterize tumors, and may hold implications for prognostication and management. Methods: We conducted a review of primary epigenetic studies of pituitary tumors with a focus on histone modification, DNA methylation, and transcript modification. Results: High levels of methylation have been identified in invasive and large pituitary tumors. DNA methyltransferase overexpression has been detected in pituitary tumors, especially in macroadenomas. Methylation differences at CpG sites in promoter regions may distinguish several types of tumors from normal pituitary tissue. Histone modifications have been linked to increased p53 expression and longer progression-free survival in pituitary tumors; sirtuins are expressed at higher values in GH-expressing compared to nonfunctional adenomas and correlate inversely with size in somatotrophs. Upregulation in citrullinating enzymes may be an early pathogenic marker of prolactinomas. Numerous genes involved with cell growth and signaling show altered methylation status for pituitary tumors, including cell cycle regulators, components of signal transduction pathways, apoptotic regulators, and pituitary developmental signals. Conclusions: The limited clinical predictive capacity of the current pituitary tumor classification system suggests that tumor subclasses likely remain to be discovered. Ongoing epigenetic studies could provide a basis for adding methylation and/or acetylation screening to standard pituitary tumor workups. Identifying robust correlations between tumor epigenetics and corresponding histological, radiographic, and clinical course information could ultimately inform clinical decision-making.

Keywords: endocrine surgery; epigenetics; epigenome; pituitary adenoma; pituitary tumor; precision medicine.

Figure 1

Pre-translational modifications that affect gene expression. Modifications that affect gene expression can occur at any point along the path from packaged DNA to protein expression. Alterations to chromosome structure or changes in chromosome copy number can affect expression at a chromosomal level. Epigenetic chromatin modifications, including histone acetylation and histone methylation, can also alter gene expression levels. At the DNA level, mutations in DNA sequence or DNA methylation can change the nature of the genes expressed as well as their level of expression. RNA transcript copy number also affects protein expression.

Figure 2

Epigenetic modifications and regulators. Epigenetic modifications are carried out by a set of specialized enzymes that act directly on DNA or on the histones around which chromatin is wrapped. Histone acetyltransferases (HATs) place acetyl groups on chromatin, while histone deacetylases (HDACs) and sirtuins do the opposite. Acetylation of histones typically upregulates gene expression, denoted here by the light blue region of DNA. DNA methyltransferases (DNMTs) and ten-eleven translocation enzymes (TETs) can alter the level of DNA or histone methylation, which typically downregulates gene expression. This is denoted by the navy-blue regions of DNA.