Endocrine Abstracts

Introduction: Epigenetic and genetic alterations contribute to cancer initiation and progression. These alterations may be playing a determinant role in the development of pituitary adenomas (PAs). One of these epigenetic processes is the DNA methylation and, specifically, methylation of Tumour Suppressor Genes (TSG). TSG are key elements that allow the maintenance of cellular homeostasis. Due to epigenetic changes are reversible, a better understanding of the underlying epigenetic alterations during tumourogenesis and the discovery of epigenetic biomarkers are essential aspects to develop new therapies in these tumours. The aim of the present study was to analyse the methylation status of 36 TSG in a series of 105 PAs using the MS-MLPA technique and quantify the gene expression of methylated genes by qRT-PCR.

Methods: The study was performed in 105 PAs (35 silent gonadotroph adenomas (SGT), 15 silent corticotroph adenomas (SCT), 15 functioning corticotroph adenomas (CT) and 40 functioning somatotroph adenomas (ST)). Clinical, pathological, and radiological data were collected anonymously for each sample from the Spanish Molecular Registry of Pituitary Adenomas (REMAH) database. Tumours were classified as aggressive (invasive or ki67≥3%) or non-aggressive (non-invasive and ki67<3%). MS-MLPA was used to analyse the promoter TSG hypermethylation. Gene expression was performed by qRT-PCR.

Results: Between the 36 TSG studied we chose the five genes with higher frequency of methylation in the overall series and in the different subtypes: TP73, CADM1, CASP8, MGMT and RASSF1. The expression of CADM1 was significant lower in SCT and in CT than in SGT (P=0.018 and P<0.001, respectively). Moreover, the expression of CADM1 was also lower in CT than in ST (P<0.001). The expression of RASSF1 was lower in ST than in SGT (P=0.014). There were no differences between subtypes in the expression of the other genes studied. TP73 was the only TSG studied whose expression correlated negatively with the aggressiveness of PAs although only in SCT subtype (P=0.037). Regrettably, methylation was associated with a decrease in the expression of TP73 only in the global series (P=0.049) but not in the SCT subtype.

Conclusions: In this series, we identified for the first time a reduction in the expression of CADM1 in the pituitary tumours derived from Tpit lineage, a subset of PAs known by its special aggressiveness compared with other subtypes. Although a larger number of SCT should be studied, it is possible that the methylation of TP73 could also contribute to the aggressiveness of this subtype of PAs.