Promoter CpG methylation of multiple genes in pituitary adenomas: frequent involvement of caspase-8

Abstract

The epigenetic changes in pituitary adenomas were identified by evaluating the methylation status of nine genes (RB1, p14 ARF , p16 INK4a , p73, MGMT, DAPK, in a series of 35 tumours using methylationspecific PCR analysis plus sequencing. The series included non-functional adenomas (n=23), prolactinomas (n=6), prolactinoma plus thyroid-stimulating hormone adenoma (n=1), growth hormone adenomas (n=4), and adrenocorticotropic adenoma (n=1). All of the tumours had methylation of at least one of these genes and 40% of samples (14 of 35) displayed concurrent methylation of at least three genes. The frequencies of aberrant methylation were: 20% for RB1, 17% for p14 ARF , 34% for p16 INK4a , 29% for p73, 11% for TIMP-3, 23% for MGMT, 6% for DAPK, 43% for THBS1 and 54% for caspase-8. No aberrant methylation was observed in two non-malignant pituitary samples from healthy controls. Although some differences in the frequency of gene methylation between functional and non-functional adenomas were detected, these differences did not reach statistical significance. Our results suggest that promoter methylation is a frequent event in pituitary adenoma tumourigenesis, a process in which inactivation of apoptosis-related genes (DAPK, caspase-8) might play a key role.

Epigenetic alterations in endocrine-related cancer

“…Interestingly, genes of the RB1 pathway were methylated in 85% of the samples, which suggests that, in addition to MEN1 mutations, methylation could be a molecular alteration that contributes to these tumors. These results were also confirmed by Bello et al (2006), who found promoter hypermethylation in the RB1, P14 (ARF), P16, and P73 genes, as well as the metalloproteinase inhibitor 3 (TIMP3), O-6-methylguanine DNA methyltransferase (MGMT), DAPK (DAPK1), THBS1, and CASP8 genes, some of which are involved in the apoptosis processes (DAPK and CASP8), DNA repair (MGMT) or have anti-angiogenic properties (THBS1). Additionally, reduced expression of the fibroblast growth factor receptor (FGFR2), a member of the FGF family with a critical role in pituitary development, in human pituitary tumors has been associated with gene promoter methylation (Zhu et al 2007).…”

High incidence of low O6-methylguanine DNA methyltransferase expression in invasive macroadenomas of Cushing's disease

“…Several studies have evaluated MGMT expression status by immunohistochemistry and/or methylationspecific PCR in pituitary adenomas (11,23,24). However, to our knowledge, this is the first report of immunohistochemical analysis of MGMT expression in corticotroph tumors from patients with Cushing's disease in which a large number of tumor samples was classified according to histologic types.…”

Correlation between BRAF mutation and promoter methylation of TIMP3, RARβ2 and RASSF1A in thyroid cancer

“…No significant correlation was found with methylation values and age groups by non-parametric Wilcoxon testing. 6,8,[11][12][13][14][15][16][17][18] Among these 19 genes, PAK3, NISCH and KIF1A were previously only tested in a small set of thyroid cancer samples by our group as a part of our comprehensive approach to discover methylated genes in cancer. 8 Three of the 22 genes, MINT1, DCC and AIM1, have not been tested in thyroid cancer to date.…”