Sporadic tumors of the pituitary, parathyroids and adrenal cortex are unique, as their benign forms are very common, but malignant forms are exceptionally rare. Hereditary forms of these tumors occur in multiple endocrine neoplasia syndrome type 1 (MEN1). We hypothesize that the pathogenic link among the sporadic tumors of these organs of different germ layers might be represented by common molecular pathways involving the MEN1 gene and microRNAs (miR). miR-24 might be a microRNA linking the three tumor entities, but other candidates such as miR-142-3p and microRNAs forming the DLK1-MEG3 miRNA cluster might also be of importance.

The brain plays a central role in organismal aging but is itself most sensitive to aging-related functional impairments and pathologies. Insights into processes underlying brain aging are the basis to positively impact brain health. Using high-throughput RNA sequencing and quantitative polymerase chain reaction (PCR), we monitored cerebral gene expression in mice throughout their whole lifespan (2, 9, 15, 24, and 30 months). Differentially expressed genes were clustered in 6 characteristic temporal expression profiles, 3 of which revealed a distinct change between 24 and 30 months, the period when most mice die. Functional annotation of these genes indicated a participation in protection against cancer and oxidative stress. Specifically, the most enriched pathways for the differentially expressed genes with higher expression at 30 versus 24 months were found to be glutathione metabolism and chemokine signaling pathway, whereas those lower expressed were enriched in focal adhesion and pathways in cancer. We therefore conclude that brains of very old mice are protected from certain aspects of aging, in particular cancer, which might have an impact on organismal health and lifespan.

Systemic treatments are tailored to breast cancer (BC) heterogeneity, which is not yet taken into account for radiotherapy (RT) personalization. The primary objective of this review is to summarize existing data suggesting BC subtypes and genetic assays are prognostic and predictive biomarkers useful for RT decision-making and to provide implications for their incorporation into future translational and clinical research. The evidence suggesting that BC subtypes also exhibit distinct "locoregional recurrence (LRR)" patterns is retrospective but consistent and validated in over fifteen studies. The HER-2 positive and triple negative subtypes are the most susceptible to locoregional failure. The high risk of the HER-2 positive subtype can be reversed with trastuzumab administration. Very little is known on the subtypes' intrinsic radiosensitivity properties. Genetic assays have assessed retrospectively signatures' prognostic and predictive value in patients' cohorts (several coming from prospective studies) for LRR risk and radiotherapy (RT) benefit. Further confirmation is needed before their introduction into clinical routine. Evidence on the use of molecular biomarkers for adjuvant RT tailoring is emerging but needs validation and introduction into prospective studies. The plethora of modern RT options (partial breast irradiation, hypofractionation), as well as recent evidence pointing towards more extensive radiotherapy, demand introduction of biological features into clinical trials to improve therapeutic decisions. Open questions, such as tailoring of irradiation after neo-adjuvant chemotherapy in complete responders and the understanding of the interplay between local control, systemic recurrence and survival given modern systemic treatments, need to be addressed under the prism of biology within this heterogeneous disease. Intrinsic radiobiological properties within this heterogeneity need to be highlighted in order to further improve outcomes.

Lung cancer remains the leading cause of cancer-related deaths in both men and women. However, the discovery of several oncogenic driver mutations and the development of immune checkpoint inhibitors resulted in improved clinical outcomes for most patients. Although activating KRAS mutations are the most common recurring molecular events in lung adenocarcinoma, little progress has been made during the past decades with no new agents being approved for this indication. The elucidation of the underlying biology of this diverse patient subgroup offers great potential and renewed hope regarding the rational development, rigorous evaluation and subsequent approval of novel targeted agents and combinations which will effectively suppress compensatory escape routes and the emergence of resistance, issues that have plagued previous attempts. Here, we review in a structured manner all aspects of KRAS positive non-small cell lung cancer, including the molecular biology, clinicopathologic characteristics, the prognostic and predictive value of KRAS mutations, as well as previous and contemporary approaches towards the treatment of this elusive target.

Resistance to hormonal therapies is a major clinical problem in the treatment of estrogen receptor α-positive (ERα+) breast cancers. Epigenetic marks, namely DNA methylation of cytosine at specific CpG sites (5mCpG), are frequently associated with ERα+ status in human breast cancers. Therefore, ERα may regulate gene expression in part via DNA methylation. This hypothesis was evaluated using a panel of breast cancer cell line models of antiestrogen resistance. Microarray gene expression profiling was used to identify genes normally silenced in ERα+ cells but derepressed upon exposure to the demethylating agent decitabine, derepressed upon long-term loss of ERα expression, and resuppressed by gain of ERα activity/expression. ERα-dependent DNA methylation targets (n = 39) were enriched for ERα-binding sites, basal-up/luminal-down markers, cancer stem cell, epithelial-mesenchymal transition, and inflammatory and tumor suppressor genes. Kaplan-Meier survival curve and Cox proportional hazards regression analyses indicated that these targets predicted poor distant metastasis-free survival among a large cohort of breast cancer patients. The basal breast cancer subtype markers LCN2 and IFI27 showed the greatest inverse relationship with ERα expression/activity and contain ERα-binding sites. Thus, genes that are methylated in an ERα-dependent manner may serve as predictive biomarkers in breast cancer.

The switch from oxidative phosphorylation to glycolysis in proliferating cancer cells, even under aerobic conditions, has been shown first in 1926 by Otto Warburg. Today this phenomenon is known as the "Warburg effect" and recognized as a hallmark of cancer. The metabolic shift to glycolysis is associated with the alterations in signaling pathways involved in energy metabolism, including glucose uptake and fermentation, and regulation of mitochondrial functions. Hexokinases (HKs), which catalyze the first step of glycolysis, have been identified to play a role in tumorigenesis of human colorectal cancer (CRC) and melanoma. However, the mechanism of action of HKs in the promotion of tumor growth remains unclear.

Various chromatin modifications, identified in large-scale epigenomic analyses, are associated with distinct phenotypes of different cells and disease phases. To improve our understanding of these variations, many computational methods have been developed to discover novel sites and cell-specific chromatin modifications. Despite the availability of existing methods, there is still room for further improvement when they are applied to resolve the histone code hypothesis. Hence, we aim to investigate the development of a computational method to provide new insights into de novo combinatorial pattern discovery of chromatin modifications to characterize epigenetic variations in distinct phenotypes of different cells.

Germline mutations in the coding sequence of the tumour suppressor APC gene give rise to familial adenomatous polyposis (which leads to colorectal cancer) and are associated with many other oncopathologies. The loss of APC function because of deletion of putative promoter 1A or 1B also results in the development of colorectal cancer. Since the regions of promoters 1A and 1B contain many single nucleotide polymorphisms (SNPs), the aim of this study was to perform functional analysis of some of these SNPs by means of an electrophoretic mobility shift assay (EMSA) and a luciferase reporter assay.

Colorectal cancer (CRC) is one of the most common malignant tumors worldwide. CRC molecular pathogenesis is heterogeneous and may be followed by mutations in oncogenes and tumor suppressor genes, chromosomal and microsatellite instability, alternative splicing alterations, hypermethylation of CpG islands, oxidative stress, impairment of different signaling pathways and energy metabolism. In the present work, we have studied the alterations of alternative splicing patterns of genes related to energy metabolism in CRC.

Functional genomic and epigenomic research relies fundamentally on sequencing based methods like ChIP-seq for the detection of DNA-protein interactions. These techniques return large, high dimensional data sets with visually complex structures, such as multi-modal peaks extended over large genomic regions. Current tools for visualisation and data exploration represent and leverage these complex features only to a limited extent.

Identifying molecular signatures of disease phenotypes is studied using two mainstream approaches: (i) Predictive modeling methods such as linear classification and regression algorithms are used to find signatures predictive of phenotypes from genomic data, which may not be robust due to limited sample size or highly correlated nature of genomic data. (ii) Gene set analysis methods are used to find gene sets on which phenotypes are linearly dependent by bringing prior biological knowledge into the analysis, which may not capture more complex nonlinear dependencies. Thus, formulating an integrated model of gene set analysis and nonlinear predictive modeling is of great practical importance.

Modeling survival oncological data has become a major challenge as the increase in the amount of molecular information nowadays available means that the number of features greatly exceeds the number of observations. One possible solution to cope with this dimensionality problem is the use of additional constraints in the cost function optimization. LASSO and other sparsity methods have thus already been successfully applied with such idea. Although this leads to more interpretable models, these methods still do not fully profit from the relations between the features, specially when these can be represented through graphs. We propose DEGREECOX, a method that applies network-based regularizers to infer Cox proportional hazard models, when the features are genes and the outcome is patient survival. In particular, we propose to use network centrality measures to constrain the model in terms of significant genes.

microRNA assessments in biological samples can be performed by different methods that mainly rely on hybridization process, qPCR or RNA sequencing. With the aim to detect and validate microRNA biomarkers in tumor samples, we challenged the consistency of the quantitative results obtained with the different methods.

Objective. To evaluate the HER2 expression on gastric adenocarcinoma from a Brazilian population and also to analyze the relations between the receptor and clinical characteristics, as well as the survival status. Materials and Methods. A retrospective analysis was conducted from January of 2008 to July of 2012, considering only gastrectomies with curative intent. Tumors were tested for HER2 status using immunohistochemistry. The relation between HER2 status and clinical aspects, surgical findings, and survival were also analyzed. Results. 222 patients with gastric carcinoma were submitted to surgery during that period, but only 121 (54,5%) were with curative intention. The immunohistochemistry revealed that 4 patients (3,3%) were HER2-positive, 6 patients (4,9%) HER2-undetermined, and 111 patients (91,7%) HER2-negative. There was no statistical concordance between HER2 status and survival or the clinical aspects. Conclusion. The HER2 overexpression rate was very low in this Brazilian population sample and cannot be considered as a prognostic factor.

Hepatocellular carcinoma (HCC) is a major public health concern and one of the leading causes of tumour-related deaths worldwide. Extensive evidence endorses that HCC is a multifactorial disease characterised by hepatic cirrhosis mostly associated with chronic inflammation and hepatitis B/C viral infections. Interaction of viral products with the host cell machinery may lead to increased frequency of genetic and epigenetic aberrations that cause harmful alterations in gene transcription. This may provide a progressive selective advantage for neoplastic transformation of hepatocytes associated with phenotypic heterogeneity of intratumour HCC cells, thus posing even more challenges in HCC treatment development. Epigenetic aberrations involving DNA methylation, histone modifications, and noncoding miRNA dysregulation have been shown to be intimately linked with and play a critical role in tumour initiation, progression, and metastases. The current review focuses on the aberrant hepatoepigenetics events that play important roles in hepatocarcinogenesis and their utilities in the development of HCC therapy.

Important links exist between the process of pre-mRNA splicing and cancer, as illustrated by the frequent mutation of splicing factors in tumors and the emergence of various families of antitumor drugs that target components of the splicing machinery, notably SF3B1, a protein subunit of spliceosomal U2 small nuclear ribonucleoprotein particle (snRNP). Sudemycins are synthetic compounds that harbor a pharmacophore common to various classes of splicing inhibitors. Here, we describe the synthesis and functional characterization of novel sudemycin analogues that functionally probe key chemical groups within this pharmacophore. Our results confirm the importance of a conjugated diene group and in addition reveal significant spatial flexibility in this region of the molecule. Sudemycin K, a derivative that replaces the pharmacophore's oxycarbonyl by an amide group, displays improved potency as an inhibitor of cancer cell proliferation, as a regulator of alternative splicing in cultured cells and as an inhibitor of in vitro spliceosome assembly. Sudemycin K displays higher stability, likely related to the replacement of the oxycarbonyl group, which can be a substrate of esterases, by an amide group. The activity and special reactivity of sudemycin K can pave the way to the synthesis and evaluation of a variety of novel sudemycin derivatives.

Lynch syndrome is the most common form of hereditary colorectal cancer, being also responsible for endometrial and other types of cancers. It is associated with germline mutations in DNA mismatch repair genes and microsatellite instability. MLH1 and MSH2 mutations have a "classical" Lynch syndrome phenotype, with MSH2 having a higher association with extracolonic cancer. MSH6 and PMS2 mutations have an atypical phenotype. Clinical expression is heterogeneous, with correlation between mismatch repair mutated gene and phenotypic patterns.