Multicenter In-House Evaluation of an Amplicon-Based Next-Generation Sequencing Panel for Comprehensive Molecular Profiling.

Background: Predicting response to targeted cancer therapies increasingly relies on both simple and complex genetic biomarkers. Comprehensive genomic profiling using high-throughput assays must be evaluated for reproducibility and accuracy compared with existing methods.

Methods: This study is a multicenter evaluation of the Oncomine™ Comprehensive Assay Plus (OCA Plus) Pan-Cancer Research Panel for comprehensive genomic profiling of solid tumors.

Extracellular Vesicles from Pancreatic Cancer Stem Cells Lead an Intratumor Communication Network (EVNet) to fuel tumour progression.

Objective: Intratumor heterogeneity drives cancer progression and therapy resistance. However, it has yet to be determined whether and how subpopulations of cancer cells interact and how this interaction affects the tumour.

Design: We have studied the spontaneous flow of extracellular vesicles (EVs) between subpopulations of cancer cells: cancer stem cells (CSC) and non-stem cancer cells (NSCC).

The Adaptive Immune Landscape of the Colorectal Adenoma-Carcinoma Sequence.

Background: The tumor immune microenvironment exerts a pivotal influence in tumor initiation and progression. The aim of this study was to analyze the immune context of sporadic and familial adenomatous polyposis (FAP) lesions along the colorectal adenoma-carcinoma sequence (ACS).

Methods: We analyzed immune cell counts (CD3+, CD4+, CD8+, Foxp3+, and CD57+), tumor mutation burden (TMB), MHC-I expression and PD-L1 expression of 59 FAP and 74 sporadic colorectal lesions, encompassing adenomas with low-grade dysplasia (LGD) (30 FAP; 30 sporadic), adenomas with high-grade dysplasia (22 FAP; 30 sporadic), and invasive adenocarcinomas (7 FAP; 14 sporadic).

The Glucocorticoid Receptor Gene () 9β SNP Is Associated with Posttraumatic Stress Disorder.

Posttraumatic stress disorder (PTSD) has been associated with glucocorticoid (GC) hypersensitivity. Although genetic factors account for 30-46% of the variance in PTSD, no associations have been found between single nucleotide polymorphisms (SNPs) of the GC receptor (GR) gene () and risk for this disorder. We studied the association of five SNPs in the GR gene (rs10052957, rs6189/rs6190, rs6195, rs41423247, and rs6198) and haplotypes with PTSD, in a group of Portuguese male war veterans (33 with lifetime PTSD, 28 without).

The Influence of the Genetic and Immunologic Context in the Development of Colorectal Adenoma: A Case Series Report.

Introduction: Overcoming immunosurveillance is a major step in the progression of many types of tumors. Several immune escape strategies have been identified, including immunoediting and the establishment of an immune suppressive microenvironment. The aim of the present study was to determine whether the hereditary or sporadic context has any influence in the relationship between immune surveillance and tumor development, using sporadic and familial adenomatous polyposis related colorectal adenomas as a model.

Genetic Variants of the MGAT5 Gene Are Functionally Implicated in the Modulation of T Cells Glycosylation and Plasma IgG Glycome Composition in Ulcerative Colitis.

Objectives: The impact of genetic variants (single nucleotide polymorphisms [SNPs]) in the clinical heterogeneity of ulcerative colitis (UC) remains unclear. We showed that patients with UC exhibit a deficiency in MGAT5 glycogene transcription in intestinal T cells associated with a hyperimmune response. Herein, we evaluated whether MGAT5 SNPs might functionally impact on T cells glycosylation and plasma IgG glycome in patients with UC, as well as in UC clinical outcomes.

Differential Modulation of Cancellous and Cortical Distal Femur by Fructose and Natural Mineral-Rich Water Consumption in Ovariectomized Female Sprague Dawley Rats.

Bone mineral density (BMD) and microstructure depend on estrogens and diet. We assessed the impact of natural mineral-rich water ingestion on distal femur of fructose-fed estrogen-deficient female Sprague Dawley rats. Ovariectomized rats drank tap or mineral-rich waters, with or without 10%-fructose, for 10 weeks.

The Two Faces of Tumor-Associated Macrophages and Their Clinical Significance in Colorectal Cancer.

Macrophages are one of the immune populations frequently found in colorectal tumors and high macrophage infiltration has been associated with both better and worst prognosis. Importantly, according to microenvironment stimuli, macrophages may adopt different polarization profiles, specifically the pro-inflammatory or M1 and the anti-inflammatory or M2, which display distinct functions. Therefore, concomitantly with the number of tumor-associated macrophages (TAMs), their characterization is fundamental to unravel their relevance in cancer.

Interaction of Genetic Variations in and Modulates the Risk of Hashimoto's Thyroiditis.

Several single-nucleotide polymorphisms (SNPs) are known to increase the risk of Hashimoto's thyroiditis (HT); such SNPs reside in thyroid-specific genes or in genes related to autoimmunity, inflammation, and/or cellular defense to stress. The transcription factor Nrf2, encoded by , is a master regulator of the cellular antioxidant response. This study aimed to evaluate the impact of genetic variation in on the risk of developing HT.

Is Low-Dose Radiation Exposure a Risk Factor for Atherosclerotic Disease?

Nontargeted late effects of radiation include an increased risk of cardiovascular disease, although this is still debatable in the context of low-dose radiation. Tinea capitis patients treated in childhood with X rays to induce scalp epilation received a low dose of radiation to their carotids. To better clarify this issue, we evaluated carotid atherosclerosis in a cohort of such patients treated in 1950-1963 in Portugal.

Association between Polymorphisms in Antioxidant Genes and Inflammatory Bowel Disease.

Inflammation is the driving force in inflammatory bowel disease (IBD) and its link to oxidative stress and carcinogenesis has long been accepted. The antioxidant system of the intestinal mucosa in IBD is compromised resulting in increased oxidative injury. This defective antioxidant system may be the result of genetic variants in antioxidant genes, which can represent susceptibility factors for IBD, namely Crohn's disease (CD) and ulcerative colitis (UC).

IL6-174 G>C Polymorphism (rs1800795) Association with Late Effects of Low Dose Radiation Exposure in the Portuguese Tinea Capitis Cohort.

Head and neck cancers, and cardiovascular disease have been described as late effects of low dose radiation (LDR) exposure, namely in tinea capitis cohorts. In addition to radiation dose, gender and younger age at exposure, the genetic background might be involved in the susceptibility to LDR late effects. The -174 G>C (rs1800795) SNP in IL6 has been associated with cancer and cardiovascular disease, nevertheless this association is still controversial.

Interleukin-1B signalling leads to increased survival of gastric carcinoma cells through a CREB-C/EBPβ-associated mechanism.

Background: Polymorphisms in inflammation-related genes have been associated with a risk of gastric carcinoma (GC). However, the biological mechanisms underlying these associations are still elusive. Our objective was to determine whether chronic inflammation-associated IL1Β signalling, as seen in the context of Helicobacter pylori infection, could be linked to gastric carcinogenesis by modulating the behaviour of gastric epithelial cells.

Quantification of mutant E-cadherin using bioimaging analysis of in situ fluorescence microscopy. A new approach to CDH1 missense variants.

Missense mutations result in full-length proteins containing an amino acid substitution that can be neutral or deleterious, interfering with the normal conformation, localization, and function of a protein. A striking example is the presence of CDH1 (E-cadherin gene) germline missense variants in hereditary diffuse gastric cancer (HDGC), which represent a clinical burden for genetic counseling and surveillance of mutation carriers and their families. CDH1 missense variants can compromise not only the function of E-cadherin but also its expression pattern.

Polymorphisms in the TNFA and IL6 genes represent risk factors for autoimmune thyroid disease.

Background: Autoimmune thyroid disease (AITD) comprises diseases including Hashimoto's thyroiditis and Graves' disease, both characterized by reactivity to autoantigens causing, respectively, inflammatory destruction and autoimmune stimulation of the thyroid-stimulating hormone receptor. AITD is the most common thyroid disease and the leading form of autoimmune disease in women. Cytokines are key regulators of the immune and inflammatory responses; therefore, genetic variants at cytokine-encoding genes are potential risk factors for AITD.

Genetic variants in the IL1A gene region contribute to intestinal-type gastric carcinoma susceptibility in European populations.

The most studied genetic susceptibility factors involved in gastric carcinoma (GC) risk are polymorphisms in the inflammation-linked genes interleukin 1 (IL1) B and IL1RN. Despite the evidence pointing to the IL1 region, definite functional variants reproducible across populations of different genetic background have not been discovered so far. A high density linkage disequilibrium (LD) map of the IL1 gene cluster was established using HapMap to identify haplotype tagSNPs.

Biomarkers for gastric cancer: prognostic, predictive or targets of therapy?

Gastric cancer is an aggressive disease often diagnosed at an advanced stage. Despite improvements in surgical and adjuvant treatment approaches, gastric cancer remains a global public health problem with a 5-year overall survival of less than 25 %. This is a heterogeneous disease, both in terms of biology and genetics, and many prognostic biomarkers have been pointed out in the literature; nevertheless, their application remains debatable.

A polymorphism in the promoter region of the selenoprotein S gene (SEPS1) contributes to Hashimoto's thyroiditis susceptibility.

Context: The association between selenium and inflammation and the relevance of selenoproteins in follicular thyroid cell physiology have pointed to a putative role of selenoproteins in the pathogenesis of autoimmune thyroid diseases.

Objective: The aim of this study was to evaluate the role of a promoter variation in SEPS1, the selenoprotein S gene, in the risk for developing Hashimoto's thyroiditis (HT).

Design: A case-control study was performed to assess the association of genetic variation in the SEPS1 gene (SEPS1 -105G/A single-nucleotide polymorphism, rs28665122) and HT.

First-degree relatives of early-onset gastric cancer patients show a high risk for gastric cancer: phenotype and genotype profile.

First-degree relatives (FDR) of early-onset gastric cancer (EOGC) is presumed to be a population with a distinct molecular and phenotypic profile, regarding the prevalence of gastric premalignant conditions and the association with Helicobacter pylori infection and host proinflammatory gene polymorphisms. A case-control study was conducted with FDR of EOGC patients (n = 103) and age and gender matched controls (n = 101; ranging from spouses to neighbors and dyspeptics). Upper endoscopy was performed, Operative Link on Gastritis Assessment (OLGA) system used for staging and H.

Phenotype-genotype profiles in Crohn's disease predicted by genetic markers in autophagy-related genes (GOIA study II).

Background: About 70 loci are associated with susceptibility to Crohn's disease (CD), particularly in pathways of innate immunity, autophagy, and pathogen recognition. Phenotype-genotype associations are inconsistent.

Methods: CD susceptibility polymorphisms ATG16L1 rs2241880, ICAM1 rs5498, IL4 rs2070874, IL17F rs763780, IRGM rs13361189, ITLN1 rs2274910, LRRK2 rs11175593, and TLR4 rs4986790 were genotyped in a Portuguese population (511 CD patients, 626 controls) and assessed for association with CD clinical characteristics.

1Alpha,25-dihydroxyvitamin D3 induces de novo E-cadherin expression in triple-negative breast cancer cells by CDH1-promoter demethylation.

Background: The triple-negative subgroup of breast cancer includes a cluster of tumors exhibiting low E-cadherin expression (metaplastic carcinomas). In several cancer models, 1 alpha,25-dihydroxyvitamin D(3) (1α,25(OH)(2)D(3)) induces differentiation by increasing E-cadherin expression. The Vitamin D receptor (VDR) was evaluated as a possible therapeutic target for metaplastic carcinomas and 1α,25(OH)(2)D(3) effects as a differentiating agent in triple-negative breast cancer cells were assessed.

C/EBP alpha expression is associated with homeostasis of the gastric epithelium and with gastric carcinogenesis.

Transcription factors from the CCAAT/enhancer-binding protein (C/EBP) family are fundamental for the control of differentiation and proliferation of many adult tissues. C/EBP alpha has a crucial role in inducing terminal differentiation and is an established tumor suppressor gene in several cancer models. The objective of this study was to analyze the putative role of C/EBP alpha in gastric carcinoma (GC).

Association between cytokine gene polymorphisms and gastric precancerous lesions: systematic review and meta-analysis.

Polymorphisms within interleukin-1 (IL1) and tumor necrosis factor alpha (TNFA) gene clusters are associated with an increased risk of gastric cancer. However, their role in gastric precancerous lesions remains poorly understood. Our objective was to perform a meta-analysis of studies addressing the association between IL1B-511, IL1RN variable number of tandem repeat, and TNFA-308 gene polymorphisms and gastric precancerous lesions, including original data from Portugal and Mozambique.