1327 Integrated Epigenomic and Gene Expression Analysis Correlates Genetic Characteristics of GH-Secreting Pituitary Adenomas to Clinical Outcomes

INTRODUCTION: Growth hormone (GH)-secreting pituitary adenomas (PA) account for approximately 20% of PAs, and often cause acromegaly. Little is known regarding DNA methylation patterns and gene expression variations in this functional PA subtype. METHODS: 57 GH-secreting PAs, surgically resected between 2010-2020, were included in this study. Profiling analysis were conducted via Illumina EPIC 850k Methylation Array and Illumina whole-transcriptome analysis for RNA sequencing (RNA-Seq). All data were analyzed in R. Sub-analyses were completed by invasion status and remission to search for differential methylation and expression. RESULTS: Our study showed clear unsupervised categorization of GH adenomas according to invasion and recurrence. In the invasion sub-analysis, the top 20 differentially methylated CpG probes included COL3A1 (p<0.0001), COL19A1 (p<0.0001), and MEF2C (p<0.0001), which were more likely to be hypermethylated in invasive PAs. In our comparative RNA-Seq results, we found COL19A1 was significantly under-expressed (p<0.0038) in invasive PAs. In the hormonal remission sub-analysis, the top 20 differentially methylated probes included UBAC2 (p<0.0001) and MXRA7 (p<0.0001), both of which were hypermethylated, and RFTN1 (p<0.0001) which was hypomethylated in non-remission patients. In our comparative RNA-Seq results, however, MXRA7 was significantly overexpressed in the non-remission group (p<0.001). In our independent expression analysis among all 57 acromegaly patients, CXCL8 (p<0.0001) was uniformly under-expressed, while RN7SK (p<0.0001) was uniformly overexpressed. CONCLUSIONS: To our knowledge, we are the first to describe differential epigenetic and expression markers related to invasion and remission in GH-secreting PAs. The hypermethylation of structural genes, such as COL3A1/COL19A1 in invasive GH-secreting PAs, and uniform under-expression of CXCL8 (IL-8), introduce novel genetic characteristics in the disease progression of GH-secreting PAs and may subserve the process of PA invasion.