Vemurafenib resistance increases melanoma invasiveness and modulates the tumor microenvironment by MMP-2 upregulation.

The BRAF(V600E) mutation confers constitutive kinase activity and accounts for >90% of BRAF mutations in melanoma. This genetic alteration is a current therapeutic target; however, the antitumorigenic effects of the BRAF(V600E) inhibitor vemurafenib are short-lived and the majority of patients present tumor relapse in a short period after treatment. Characterization of vemurafenib resistance has been essential to the efficacy of next generation therapeutic strategies.

Hypoxia-mediated upregulation of MCT1 expression supports the glycolytic phenotype of glioblastomas.

Background: Glioblastomas (GBM) present a high cellular heterogeneity with conspicuous necrotic regions associated with hypoxia, which is related to tumor aggressiveness. GBM tumors exhibit high glycolytic metabolism with increased lactate production that is extruded to the tumor microenvironment through monocarboxylate transporters (MCTs). While hypoxia-mediated regulation of MCT4 has been characterized, the role of MCT1 is still controversial.

Isolation, characterization and screening of the in vitro cytotoxic activity of a novel L-amino acid oxidase (LAAOcdt) from Crotalus durissus terrificus venom on human cancer cell lines.

An L-amino acid oxidase (LAAOcdt) from Crotalus durissus terrificus venom was purified to homogeneity in a two-step procedure using molecular exclusion on Sephadex G-75, followed by Phenyl Sepharose FF chromatography. The molecular mass of the purified enzyme was 113 kDa, as determined by SDS-PAGE under reducing conditions. LAAOcdt showed amino acid homology to other L-amino acid oxidases isolated from different snake venoms.

Oncogenetics service and the Brazilian public health system: the experience of a reference Cancer Hospital.

The identification of families at-risk for hereditary cancer is extremely important due to the prevention potential in those families. However, the number of Brazilian genetic services providing oncogenetic care is extremely low for the continental dimension of the country and its population. Therefore, at-risk patients do not receive appropriate assistance.

Copy Number Profiling of Brazilian Astrocytomas.

Copy number alterations (CNA) are one of the driving mechanisms of glioma tumorigenesis, and are currently used as important biomarkers in the routine setting. Therefore, we performed CNA profiling of 65 astrocytomas of distinct malignant grades (WHO grade I-IV) of Brazilian origin, using array-CGH and microsatellite instability analysis (MSI), and investigated their correlation with TERT and IDH1 mutational status and clinico-pathological features. Furthermore, in silico analysis using the Oncomine database was performed to validate our findings and extend the findings to gene expression level.

The metabolic microenvironment of melanomas: Prognostic value of MCT1 and MCT4.

BRAF mutations are known drivers of melanoma development and, recently, were also described as players in the Warburg effect, while this reprogramming of energy metabolism has been identified as a possible strategy for treating melanoma patients. Therefore, the aim of this work was to evaluate the expression and prognostic value of a panel of glycolytic metabolism-related proteins in a series of melanomas. The immunohistochemical expression of MCT1, MCT4, GLUT1, and CAIX was evaluated in 356 patients presenting melanoma and 20 patients presenting benign nevi.

Brachyury as a potential modulator of androgen receptor activity and a key player in therapy resistance in prostate cancer.

Prostate cancer (PCa) is the most commonly diagnosed neoplasm and the second leading cause of cancer-related deaths in men. Acquisition of resistance to conventional therapy is a major problem for PCa patient management. Several mechanisms have been described to promote therapy resistance in PCa, such as androgen receptor (AR) activation, epithelial-to-mesenchymal transition (EMT), acquisition of stem cell properties and neuroendocrine transdifferentiation (NEtD).

Anti-EGFR Therapy: Strategies in Head and Neck Squamous Cell Carcinoma.

Epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor that activates downstream signaling pathways, including the Ras-MEK-Erk and PI3K-AKT pathways, leading to cell proliferation, resistance to apoptosis, angiogenesis and the ability to metastasize. EGFR overexpression is a significant finding in cancer, particularly in head and neck cancer, where it is also associated with a poor prognosis. In recent years, several molecules have been designed to inhibit EGFR activation.

Cytotoxicity of allitinib, an irreversible anti-EGFR agent, in a large panel of human cancer-derived cell lines: KRAS mutation status as a predictive biomarker.

Background: The epidermal growth factor receptor (EGFR) is a member of the HER family of growth factors that activates several intracellular signaling pathways promoting proliferation and survival. EGFR over-expression is frequently associated with gene mutation or amplification, thereby constituting a major target for molecular therapies. Recently, a new generation of EGFR inhibitors has been developed with pan-HER properties and irreversible actions.

The prognostic impact of TERT promoter mutations in glioblastomas is modified by the rs2853669 single nucleotide polymorphism.

Human hotspot TERT promoter (TERTp) mutations have been reported in a wide range of tumours. Several studies have shown that TERTp mutations are associated with clinicopathological features; in some instances, TERTp mutations were considered as biomarkers of poor prognosis. The rs2853669 SNP, located in the TERT promoter region, was reported to modulate the increased TERT expression levels induced by the recurrent somatic mutations.

Brachyury identifies a class of enteroendocrine cells in normal human intestinal crypts and colorectal cancer.

Normal homeostasis of adult intestinal epithelium and repair following tissue damage is maintained by a balance of stem and differentiated cells, many of which are still only poorly characterised. Enteroendocrine cells of the gut are a small population of differentiated, secretory cells that are critical for integrating nutrient sensing with metabolic responses, dispersed amongst other epithelial cells. Recent evidence suggests that sub-sets of secretory enteroendocrine cells can act as reserve stem cells.

Raf Kinase Inhibitor Protein Expression and Prognostic Value in Soft Tissue Sarcomas.

Objective: Soft tissue sarcomas (STSs) are heterogeneous tumors displaying multiple and complex molecular abnormalities with no specific pattern. Despite current therapeutic advances, the patients with STS still have a poor outcome, which makes it necessary to find out new prognostic markers. The Raf kinase inhibitory protein (RKIP) has been associated with prognosis in several human neoplasms; however, its role in STS is unknown.

Molecular profiling, including TERT promoter mutations, of acral lentiginous melanomas.

Acral lentiginous melanoma (ALM) is the less common subtype with singular characterization. TERT (human telomerase reverse transcriptase) promoter mutations have being described as recurrent in melanomas and infrequent in ALM, but their real incidence and clinical relevance is unclear. The objectives of this study were to describe the prevalence of TERT promoter mutations in ALM, and correlate with the molecular profile of other drive genes and clinical features.

Lactate Transporters and pH Regulation: Potential Therapeutic Targets in Glioblastomas.

Despite advances in therapy, glioblastoma (GBM) is still the most prevalent and lethal brain tumor. Thus, it is imperative to identify new and effective therapies that could improve the lifetime of these patients. It is known that tumor cells, such as glioblastomas present metabolic reprogramming, named "Warburg effect", recognized nowadays as a hallmark of cancer.

Ancestry of the Brazilian TP53 c.1010G>A (p.Arg337His, R337H) Founder Mutation: Clues from Haplotyping of Short Tandem Repeats on Chromosome 17p.

Rare germline mutations in TP53 (17p13.1) cause a highly penetrant predisposition to a specific spectrum of early cancers, defining the Li-Fraumeni Syndrome (LFS). A germline mutation at codon 337 (p.

Hotspot TERT promoter mutations are rare events in testicular germ cell tumors.

The abnormal activation of telomerase, codified by the telomerase reverse transcriptase (TERT) gene, is related to one of cancer hallmarks. Hotspot somatic mutations in the promoter region of TERT, specifically the c.-124:C>T and c.

Glucose Addiction in Cancer Therapy: Advances and Drawbacks.

While normal differentiated cells primarily use mitochondrial respiration to generate the required energy for cellular processes, most cancer cells rely on glycolysis, even in sufficient oxygen conditions. This phenomenon is known as the "Warburg effect" or aerobic glycolysis and the metabolic reprogramming of cancer cells towards this altered energy metabolism is currently recognized as one of the "hallmarks of cancer". Aerobic glycolysis underlies the rapid growth of tumor cells, with high rates of glucose consumption and lactic acid production, leading to cellular acidosis.

Transcriptional profiling of HOXA9-regulated genes in human glioblastoma cell models.

The data here described pertain to the article by Pojo et al. (2015) [10] titled “A transcriptomic signature mediated by HOXA9 promotes human glioblastoma initiation, aggressiveness and resistance to temozolomide” (Pojoet al., 2015 [10]).

SPINT2 Deregulation in Prostate Carcinoma.

SPINT2 is a tumor suppressor gene that inhibits proteases implicated in cancer progression, like HGFA, hepsin and matriptase. Loss of SPINT2 expression in tumors has been associated with gene promoter hypermethylation; however, little is known about the mechanisms of SPINT2 deregulation in prostate cancer (PCa). We aimed to analyze SPINT2 expression levels and understand the possible regulation by SPINT2 promoter hypermethylation in PCa.

TERT promoter mutations in soft tissue sarcomas.

Introduction: Oncogenic hotspot mutations in the promoter region of the TERT gene have been identified in several cancer types as being associated with a worse outcome. Additionally, a polymorphism (rs2853669) in the TERT promoter region was reported to modify the survival of TERT-mutated patients. Our aim is to determine the frequency of c.

Molecular Profiling of a Rare Rosette-Forming Glioneuronal Tumor Arising in the Spinal Cord.

Rosette-forming glioneuronal tumor (RGNT) of the IV ventricle is a rare and recently recognized brain tumor entity. It is histologically composed by two distinct features: a glial component, resembling pilocytic astrocytoma, and a component forming neurocytic rosettes and/or perivascular rosettes. Herein, we describe a 33-year-old man with RGNT arising in the spinal cord.

Type 2 diabetes-related variants influence the risk of developing multiple myeloma: results from the IMMEnSE consortium.

Type 2 diabetes (T2D) has been suggested to be a risk factor for multiple myeloma (MM), but the relationship between the two traits is still not well understood. The aims of this study were to evaluate whether 58 genome-wide-association-studies (GWAS)-identified common variants for T2D influence the risk of developing MM and to determine whether predictive models built with these variants might help to predict the disease risk. We conducted a case-control study including 1420 MM patients and 1858 controls ascertained through the International Multiple Myeloma (IMMEnSE) consortium.

Expression of Methylthioadenosine Phosphorylase (MTAP) in Pilocytic Astrocytomas.

Background/objectives: Pilocytic astrocytomas (PAs) are the most frequent astrocytomas in children and adolescents. Methilthioadenosine phosphorylase(MTAP) is a tumor-suppressor gene, the loss of expression of which is associated with a poor prognosis and better response to specific chemotherapy in leukemia and non-small-cell lung cancer. The expression of MTAP in brain tumors remains largely unknown and its biological role in PA is still unexplored.

KIAA1549: BRAF Gene Fusion and FGFR1 Hotspot Mutations Are Prognostic Factors in Pilocytic Astrocytomas.

Up to 20% of patients with pilocytic astrocytoma (PA) experience a poor outcome. BRAF alterations and Fibroblast growth factor receptor 1 (FGFR1) point mutations are key molecular alterations in Pas, but their clinical implications are not established. We aimed to determine the frequency and prognostic role of these alterations in a cohort of 69 patients with PAs.

The embryonic Brachyury transcription factor is a novel biomarker of GIST aggressiveness and poor survival.

Background: The T-box transcription factor Brachyury was recently reported to be upregulated and associated with prognosis in solid tumors. Here, we proposed to evaluate the potential use of Brachyury protein expression as a new prognostic biomarker in gastrointestinal stromal tumors (GIST).

Methods: Brachyury protein expression was analyzed by immunohistochemistry in a cohort of 63 bona fide GIST patients.