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Context: Epigenetic alterations may play a role in the development and behavior of pituitary neuroendocrine tumors (PitNETs). Objective: To evaluate the effect of methylation of tumor suppressor genes (TSGs) on their gene expression and on the behavior of PitNETs. Material and Methods: We used methylation-specific multiplex ligation-dependent probe amplification and quantitative real-time PCR techniques to analyze the DNA-promoter hypermethylation and gene expression of 35 TSGs in 105 PitNETs. We defined functionality, size, and invasiveness of tumors according to their clinical manifestations, Hardy's classification, and MRI invasiveness of the cavernous sinus, respectively. Results: We observed different methylation patterns among PitNET subtypes. The methylation status of TP73 correlated negatively with its gene expression in the overall series (P = 0.013) and in some subtypes. MSH6 and CADM1 showed higher methylation frequency in macroadenomas than in microadenomas in the overall series and in corticotroph PitNETs (all P 0.053). ESR1 and RASSF1 were more highly methylated in noninvasive than in invasive tumors in the overall series (P = 0.054 and P = 0.031, respectively) and in the gonadotroph subtype (P = 0.055 and P = 0.050, respectively). ESR1 and CASP8 appeared more hypermethylated in functioning than in silent corticotroph tumors (P = 0.034 and P = 0.034, respectively). Conclusions: NA methylation of TSGs has a selective effect on their gene expression and on the growth and invasiveness of PitNETs. Its involvement in their functionality is biased because all silent operated tumors are macroadenomas, whereas all operated microadenomas are functioning ones. Therefore, the subtypes of PitNETs should be considered different entities.

Breast cancer (BC) is one of the most frequent malignancies in women (Jemal et al, 2008). HER2 overexpressing and/or gene amplified tumours represent approximately 25% of all BC, and they are associated with an aggressive phenotype, metastases, resistance to chemotherapy (CT), and poor prognosis (Slamon et al, 1987, 1989; Peiro et al, 2007; Nguyen et al, 2008). Nevertheless, the outcome has changed dramatically with the introduction of trastuzumab, a humanised monoclonal antibody that targets the HER2 extracellular domain (Murphy and Modi, 2009). It is very effective in combination with CT for the treatment of early stages (Viani et al, 2007) or metastatic BC (Pegram et al, 2004; Brufsky et al, 2005), and even as a single-agent for the later group (Vogel et al, 2002), showing in both groups of patients a substantial decrease in cancer recurrence and mortality (Slamon et al, 2001; Piccart-Gebhart et al, 2005; Joensuu et al, 2006; Untch et al, 2008). Despite its demonstrated clinical benefit, about 30–50% of patients do not respond, and those with metastasis that achieved an initial response to trastuzumab-based regimens will develop drug resistance. Currently, in clinical practice there are not conclusive biomarkers that allow the selection of patients who will respond to trastuzumab and the exact molecular mechanisms are still not well defined. Several growth factor receptors and signalling molecules have been proposed to be responsible for trastuzumab resistance, such as downregulation of the surface HER2 protein by endocytosis and degradation (Austin et al, 2004), p27 downregulation (Lane et al, 2001; Nahta et al, 2004), activation of insulin-like growth factor 1-receptor (IGF1R) (Lu et al, 2001; Nahta et al, 2005), interaction between HER2 and epidermal growth factor 1-receptor (EGFR) (Diermeier et al, 2005), phosphatase and tensin homologue (PTEN) loss (Nagata et al, 2004), phosphoinositide 3-kinase (PI3K)/Akt activation (Esteva et al, 2011; Razis et al, 2011), MUC1 (Fessler et al, 2009) and MUC4 upregulation (Nagy et al, 2005), and the crosstalk with the ER signalling pathway (Slamon et al, 2001). More recently, the non-receptor tyrosine kinase c-SRC (SRC) has been suggested as a potential key modulator of trastuzumab response (Zhang et al, 2011). Therefore, the aim of our study was to evaluate the relevance of alterations in the PI3K/Akt/mTOR and Ras/mitogen-activated protein kinase (MAPK) signalling pathways, given their role in cell cycle progression. We performed an extensive immunohistochemical and molecular analysis of several biological markers related with these pathways, in a series of patients with HER2-positive BC in stage I-IV, to determine their prognostic relevance, and as a result, their potential involvement in the mechanisms of response to trastuzumab.

Some pituitary adenomas (PA) demonstrate aggressive behavior with local invasion and recurrences. Angiogenesis is regarded as an essential step in the formation of solid tumors. The aim of this study is to find out whether angiogenic factors may have information about the aggressiveness of PA that could be useful in determining the frequency of follow-up and whether adjuvant therapy is necessary. In this retrospective descriptive study, we evaluated vascular endothelial growth factors (VEGF) and VEGF receptor (KDR) mRNA expression by RT-PCR analysis on 46 human PA samples. Clinical data, histological subtype and radiologic characteristics were studied to determine the associations between the variables and the pre-operative behavior of the tumor. In addition, we monitored 12 patients without adjuvant post-operative therapies over 46 months after surgery, determining progression of tumor remnants and its association with these markers. VEGF expression correlates with KDR expression (r = 0.40, p = 0.006). VEGF demonstrates different expression between histological subtypes (p = 0.036). The extension at magnetic resonance imaging showed that VEGF expression was related to suprasellar extension (p = 0.007), being expressed more on tumors with extrasellar growth than intrasellar ones (p = 0.008). Our results demonstrate a 27.5 times increased risk of extrasellar growth when VEGF expression exceeds 0.222 normalized copy number (NCN) (p = 0.002). Likewise, tumors with KDR greater than 0.750 NCN had less recurrence-free survival time (p = 0.032). Our results suggest that the expression of VEGF and its receptor could be a marker for poor outcome after partial tumor resection. These data should be considered in future studies evaluating angiogenic factors as therapeutic targets in patients with PA.

INTRODUCTION AND OBJECTIVE: The ability to predict recurrence of pituitary adenoma (PA) after surgery may be helpful to determine follow-up frequency and the need for adjuvant treatment. The purpose of this study was to assess the prognostic capacity of pituitary tumor transforming gene (PTTG), insulin-like growth factor 1 receptor (IGF1R), and Ki-67. MATERIALS AND METHODS: In this retrospective study, the normalized copy number (NCN) of PTIG and IGF1R mRNA was measured using RT-PCR, and the Ki-67 index was measured by immunohistochemistry in 46 PA samples. Clinical data, histological subtype, and radiographic characteristics were collected to assess associations between variables and tumor behavior. Progression of tumor remnants and its association to markers was also studied in 14 patients with no adjuvant treatment after surgery followed up for 46±36 months. RESULTS: Extrasellar tumors had a lower PTTG expression as compared to sellar tumors (0.065 [1st-3rd quartile: 0.000-0.089] NCN vs. 0.135 [0.105-0.159] NCN, p=0.04). IGF1R expression changed depending on histological subtype (p=0.014), and was greater in tumor with remnant growth greater than 20% during follow-up (10.69±3.84 NCN vs. 5.44±3.55 NCN, p=0.014). CONCLUSIONS: Our results suggest that the IGF1R is a more helpful molecular marker than PTTG in PA management. Ki-67 showed no association to tumor behavior. However, the potential of these markers should be established in future studies with standardized methods and on larger samples.

The pathogenesis of pituitary tumours is far to be understood. Pituitary transforming tumour gene (PTTG), a gen that induces aneuploidy, genetic instability, cellular proliferation and to stimulate angiogenesis, has been involved in neoplasic transformation and shown overexpressed in many neoplasm as lung, breast, endometrium, thyroid and colon malignant tumours. On the other hand, PTTG has been inconsistently studied in pituitary tumours. The majority of studies have been performed in animals and there is a great variability in the methods used in its determination. The goal of this review is to resume the role of PTTG in tumourogenesis and critically to revise the studies published in humans in order to advance in the knowledge of the pathogenesis of pituitary adenomas and to find clinical useful predictors of the behavior of these tumours.