Potential new cancer biomarkers revealed by quantum chemistry associated with bioinformatics in the study of selectin polymorphisms.

Understanding the complex mechanisms involved in diseases caused by or related to important genetic variants has led to the development of clinically useful biomarkers. However, the increasing number of described variants makes it difficult to identify variants worthy of investigation, and poses challenges to their validation. We combined publicly available datasets and open source robust bioinformatics tools with molecular quantum chemistry methods to investigate the involvement of selectins, important molecules in the cell adhesion process that play a fundamental role in the cancer metastasis process.

rs6198 Variant May Be Involved in the Relationship of Graves' Disease with Stressful Events.

Although stressful events are known to trigger Graves' disease (GD), the mechanisms involved in this process are not well understood. The gene, encoding for the glucocorticoid receptor (GR), presents single nucleotide polymorphisms (SNPs) that are associated with stress-related diseases. To investigate the relationship between SNPs, GD susceptibility, and clinical features, we studied 792 individuals, including 384 patients, among which 209 presented with Graves' orbitopathy (GO), and 408 paired healthy controls.

Alternation between toxic and proliferative effects of Roundup® on human thyroid cells at different concentrations.

Endocrine-disrupting and carcinogenic effects of glyphosate have long been suspected, but little is known about the effect of compounds used in real life at different concentrations, neither in normal nor in thyroid tumor cells. As cancer cells may have different sensitivities and the effect of the product containing glyphosate may be different from that produced by the active ingredient alone, including the Acceptable Occupational Exposure Level (AOEL=160µg/L) and the Acceptable Daily Intake (ADI=830µg/L) determined by ANVISA, we used two human thyroid-derived cell lines, Nthy-ori 3-1 (from normal follicular cells) and TPC-1 (from papillary carcinoma), to test 15 different concentrations of Roundup® Original DI. Trypan blue (TB), CCK-8 and BrdU assays were used to evaluate cytotoxicity, metabolic activity and proliferation with 24h and 48h exposures in technical and biological triplicates.

Clinical utility of the imunohistochemical co-expression of p53 and MDM2 in thyroid follicular lesions.

In order to investigate the possible correlation between p53 and MDM2 co-expression with clinicopathological features of differentiated thyroid cancer (DTC) and its use as diagnostic and/or prognostic markers, we used immunohistochemistry to evaluate 317 thyroid samples including 208 DTC and 94 benign nodules, in addition to 15 normal tissues. MDM2 and p53 expression were highly associated (r = 0.7161; p < 0.

Clinical utility of and its receptors ( and ) in thyroid nodules: evaluation based on single nucleotide polymorphisms and mRNA analysis.

Objective: Abnormalities involving the gene and its receptors are common in several types of cancer and often related to tumor progression. We investigated the role of single nucleotide polymorphisms (SNP) in the susceptibility to cancer, their impact on its features, as well as the role of mRNA expression of these genes in thyroid malignancy.

Methods: We genotyped , , and SNPs in 157 papillary thyroid cancer (PTC) patients and 200 healthy controls.

The polymorphic inheritance of rs225014 may predict body weight variation after Graves' disease treatment.

Objective: We aimed to investigate the role of polymorphisms rs225014 and rs12885300 in Graves' disease patients, mainly for controlling body weight following treatment.

Methods: We genotyped 280 GD patients by the time of diagnosis and 297 healthy control individuals using a TaqMan SNP Genotyping technique. We followed up 141 patients for 18.

Polymorphisms of IL-4 and IL-4R are associated to some demographic characteristics of differentiated thyroid cancer patients but are not determinants of risk in the Brazilian population.

Background: IL-4 is known to present abnormal expression in thyroid tumors and SNPs in the IL-4 and its receptor IL-4R genes are associated to risk and mortality of various types of cancer.

Methods: In order to evaluate their role in differentiated thyroid cancer (DTC), we investigated genetic frequencies of two IL-4 promoter SNPs (rs2070874 C>T, rs2243250 C>T) and four non-synonymous SNPs of the IL-4R gene (rs1805010 A>G, rs1805012 C>T, rs1805013 C>T, rs1801275 A>G) in 300 DTC patients matched to 300 controls. All patients were managed according to current guidelines and followed-up for a period of 12-252 months (69.

Polymorphisms of the genes CTLA4, PTPN22, CD40, and PPARG and their roles in Graves' disease: susceptibility and clinical features.

Purpose: CTLA4, PTPN22, and CD40 are immune-regulatory genes strongly associated with GD, as well as PPARG, but their clinical significance in different populations is still uncertain.

Methods: We genotyped 282 Brazilian GD patients (234 women and 48 men, 39.80 ± 11.

Epstein-Barr virus induces morphological and molecular changes in thyroid neoplastic cells.

Although the evolution of differentiated thyroid cancer (DTC) is usually indolent, some tumors grow fast, metastasize, and may be fatal. Viruses have been associated with many human tumors, especially the Epstein-Barr virus (EBV), which shows a high viral load in DTC. In order to evaluate the ability of the virus to cause morphological and molecular changes in neoplastic thyroid cell lines TPC-1, BCPAP, and 8505C, a viral adaptation was performed for the analysis of EBV cytopathic effect (CPE), viral kinetics and gene expression analysis of oncogenes KRAS, NRAS, HRAS, and TP53.

RORγt may Influence the Microenvironment of Thyroid Cancer Predicting Favorable Prognosis.

We aimed to investigate the role of RORγt (Retinoic acid-related orphan receptor gamma) in the tumor microenvironment of differentiated thyroid carcinoma. We retrospectively analyzed 56 patients (48 papillary and 8 follicular thyroid carcinomas). Immunohistochemical expression of RORγt was compared to other immune markers previously investigated by our group, clinical and pathological information.

Genotype and phenotype landscape of MEN2 in 554 medullary thyroid cancer patients: the BrasMEN study.

Multiple endocrine neoplasia type 2 (MEN2) is an autosomal dominant genetic disease caused by RET gene germline mutations that is characterized by medullary thyroid carcinoma (MTC) associated with other endocrine tumors. Several reports have demonstrated that the RET mutation profile may vary according to the geographical area. In this study, we collected clinical and molecular data from 554 patients with surgically confirmed MTC from 176 families with MEN2 in 18 different Brazilian centers to compare the type and prevalence of RET mutations with those from other countries.

ID Proteins May Reduce Aggressiveness of Thyroid Tumors.

ID genes have an important function in the cell cycle, and ID proteins may help identify aggressive tumors, besides being considered promising therapeutic targets. However, their role in thyroid tumors is still poorly understood. We examined ID expression and their correlation with diagnostic and prognostic features aiming to find a clinical application in differentiated thyroid carcinoma (DTC) cases.

Diagnostic utility of DREAM gene mRNA levels in thyroid tumours.

Objective: The transcriptional repressor DREAM is involved in thyroid-specific gene expression, thyroid enlargement and nodular development, but its clinical utility is still uncertain. In this study we aimed to investigate whether DREAM mRNA levels differ in different thyroid tumors and how this possible difference would allow the use of DREAM gene expression as molecular marker for diagnostic and/or prognosis purpose.

Materials And Methods: We quantified DREAM gene mRNA levels and investigated its mutational status, relating its expression and genetic changes to diagnostic and prognostic features of 200 thyroid tumors, being 101 malignant [99 papillary thyroid carcinomas (PTC) and 2 anaplastic thyroid carcinomas] and 99 benign thyroid lesions [49 goiter and 50 follicular adenomas (FA)].

Investigation on the association between thyroid tumorigeneses and herpesviruses.

Herpesviruses have been associated with various human malignancies and with thyroid autoimmunity. Aiming to investigate the presence of these viruses in thyroid nodules, we analyzed serum and thyroid tissue from 183 patients (83 benign and 100 malignant thyroid nodules). We also obtained 104 normal thyroid tissues extracted from the contralateral lobe of these patients.

Gene expression of thyroid-specific transcription factors may help diagnose thyroid lesions but are not determinants of tumor progression.

Purpose: The role of thyroid-specific transcription factors in thyroid malignancy is still poorly understood, so we investigate thyroid-specific transcription factors gene expression both in benign and in malignant thyroid nodules, aiming to study a possible clinical utility of these molecules.

Methods: We quantified TTF-1, FOXE1 and PAX8 mRNA levels, relating their expression to diagnostic and prognostic features of thyroid tumors. RNA was extracted from 4 normal thyroid tissues, 101 malignant [99 papillary thyroid carcinomas (PTC) and 2 anaplastic thyroid carcinomas] and 99 benign thyroid lesion tissues [49 goiter and 50 follicular adenomas (FA)].

Polymorphisms of cell cycle control genes influence the development of sporadic medullary thyroid carcinoma.

Background: The role of key cell cycle regulation genes such as, CDKN1B, CDKN2A, CDKN2B, and CDKN2C in sporadic medullary thyroid carcinoma (s-MTC) is still largely unknown.

Methods: In order to evaluate the influence of inherited polymorphisms of these genes on the pathogenesis of s-MTC, we used TaqMan SNP genotyping to examine 45 s-MTC patients carefully matched with 98 controls.

Results: A multivariate logistic regression analysis demonstrated that CDKN1B and CDKN2A genes were related to s-MTC susceptibility.

TSHR intronic polymorphisms (rs179247 and rs12885526) and their role in the susceptibility of the Brazilian population to Graves' disease and Graves' ophthalmopathy.

Purpose: Intronic thyroid-stimulating hormone receptor polymorphisms have been associated with the risk for both Graves' disease and Graves' ophthalmopathy, but results have been inconsistent among different populations. We aimed to investigate the influence of thyroid-stimulating hormone receptor intronic polymorphisms in a large well-characterized population of GD patients.

Methods: We studied 279 Graves' disease patients (231 females and 48 males, 39.

The influence of the environment on the development of thyroid tumors: a new appraisal.

Most epidemiological studies concerning differentiated thyroid cancers (DTC) indicate an increasing incidence over the last two decades. This increase might be partially explained by the better access to health services worldwide, but clinicopathological analyses do not fully support this hypothesis, indicating that there are carcinogenetic factors behind this noticeable increasing incidence. Although we have undoubtedly understood the biology and molecular pathways underlying thyroid carcinogenesis in a better way, we have made very little progresses in identifying a risk profile for DTC, and our knowledge of risk factors is very similar to what we knew 30-40 years ago.

Genes of detoxification are important modulators of hereditary medullary thyroid carcinoma risk.

Context: Different inherited profiles of genes involved in cellular mechanisms of activation and detoxification of carcinogenic products can provide specific protection or determine the risk for cancer. Low-penetrance polymorphic genes related to the biotransformation of environmental toxins have been associated with susceptibility to and the phenotype of, human tumours.

Objective: To investigate the role of germline inheritance of polymorphisms in CYP1A2*F, CYP1A1 m1, GSTP1, NAT2 and TP53 genes in hereditary medullary thyroid carcinoma (HMTC) patients.

Evidence that polymorphisms in detoxification genes modulate the susceptibility for sporadic medullary thyroid carcinoma.

Aim: Polymorphic low-penetrance genes have been consistently associated with the susceptibility to a series of human tumors, including differentiated thyroid cancer.

Methods: To determine their role in medullary thyroid cancer (MTC), we used TaqMan SNP method to genotype 47 sporadic MTC (s-MTC) and a control group of 578 healthy individuals for CYP1A2*F, CYP1A1m1, GSTP1, NAT2 and 72TP53. A logistic regression analysis showed that NAT2C/C (OR=3.

Herpesvirus type 7 infection may play an important role in individuals with a genetic profile of susceptibility to Graves' disease.

Objective: An inherited profile of genes related to the response to aggressive environmental factors such as viruses and chemicals may be related to an increased susceptibility to Graves' disease (GD).

Design And Methods: This prospective case-control study was designed to examine the relationship between human herpesviruses (HHV) infection, determined by circulating DNA; tumour protein p53 (TP53) apoptotic ability; and detoxification system genes, and GD. We studied 280 confirmed GD patients paired to 284 controls with respect to environmental exposure.

Role of the N-acetyltransferase 2 detoxification system in thyroid cancer susceptibility.

Purpose: Genetic polymorphisms in genes encoding for enzymes involved in the biotransformation of carcinogens have been shown to be relevant as risk for cancer and may be of considerable importance from a public health point of view. Considering that N-acetyltransferase 2 (NAT2) polymorphisms modulate the response to ionizing radiation, the strongest risk factor recognized to cause differentiated thyroid cancer (DTC) thus far, we sought to determine the influence of NAT2 detoxification system on thyroid cancer susceptibility.

Experimental Design: We conducted a prospective case-control study, comparing 195 patients presenting with DTC that were previously genotyped for GSTT1, GSTM1, GSTP1, and CYP1A1, comprising 164 papillary carcinomas and 31 follicular carcinomas, with 196 control individuals paired for gender, age, ethnicity, diet routine, lifetime occupational history, smoking history, general health conditions, and previous diseases.

Lack of influence of glutathione S-transferase genotype profile on cancer susceptibility in smokers and nonsmokers.

Background: The glutathione-S-transferase (GST) gene family has an important role in the biotransformation and detoxification of different xenobiotics and endogenous carcinogens. GST profile has been associated to an increased risk for several types of tumors in different populations, but ethnic stratification makes data interpretation difficult. The Brazilian population represents a unique model in which the types and frequencies of GST gene polymorphisms are less influenced by ethnicity.

Genetic polymorphisms associated with cigarette smoking and the risk of Graves' disease.

Objective: Cigarette smoking is a well-recognized risk factor of Graves' disease and, particularly, Graves' ophthalmopathy. Hence, germline polymorphisms of detoxification genes and genes belonging to the major DNA repair-apoptosis pathways might have an important role in disease susceptibility. In addition, as some of these genes are regulated by thyroid hormones, they may affect the patients' outcomes.