GENE-07. GENOMIC ENHANCER METHYLATION IS ASSOCIATED WITH BIOLOGICAL AND CLINICAL FEATURES IN PITUITARY TUMORS

The importance of enhancers has been recently highlighted in a pan-can transcriptomic analysis that revealed causal interaction between active enhancers and actionable genes as well as their prognostic value. DNA methylation is associated with enhancer activity and its interplay with the transcriptional machinery. However, pituitary tumors (PT) were not included in the pan-can study and the role of enhancer in these tumors is unknown. In order to address the methylation profile of causal (CausEnhs) and prognostic enhancers (PrognEnhs) described in the pan-can analysis, we analyzed the DNA methylome of two cohorts - an internal one comprised of 9 macroadenomas (6 nonfunctioning pituitary tumors-NFPT and 3 functioning - FPT; 5 invasive) and 5 non-tumoral pituitary specimens (NT) and an external cohort comprised of 24 PTs (18 NFPT + 6FPTs). Unsupervised analysis showed that PrognEnhs clustered according to PT functional status and were mainly hypermethylated in NFPT in relation to FPT, in both cohorts. PrognEnhs overlapped with differentially methylated enhancers (DME) that we previously identified in a supervised analysis comparing NFPTs and FPT from our cohort (p < 0.03). Among the 6758 PrognEnhs, 177 overlapped hypermethylated enhancers and 8 overlapped hypomethylated enhancers in NFPTs. Motif analysis of the ProgEnhs that overlapped hypermethylated enhancers identified a DNA signature including the core Basic Leucine Zipper Domain (bZIP domain), binding site for the transcription factors Fra-1/Fra-2,AP-1, Fosl2 and ATF3 (p-value < 0.0001), related to various oncogenic processes. In both cohorts, probes nearest or overlapping CausEnhs were mostly hypermethylated but not significantly associated with any clinical feature. These preliminary findings suggest that DNA methylation of enhancers associated with prognosis in other tumors may be involved in the functional status and oncogenic pathways in PT.