Viral agents and their correlation with the genetic profile of predisposition to human neoplastic and autoimmune diseases

Herpesviruses (HHV) are ubiquitous, have broad tissue tropism and have been found in the thyroid, which can be a reservoir of latent HHV. HHV are considered potential carcinogenic agents and have been identified in many malignancies. More recently, they have also been associated to a series of autoimmune conditions. TP53 gene plays a critical role in cell cycle control, facilitating DNA repair activities and protecting against DNA damages. HHV infected cells may gain a dangerous survival time in individuals with impairing apoptotic ability, such as that caused by TP53 gene polymorphisms. Other genes involved in the response to environmental aggressions, such as the genes that codify the Glutathione S-Trans ferase (GST) and other enzymatic protective systems, may modulate the risk of developing diseases. We recently demonstrated an increased risk for HHV6 infection in individuals that inherited a codon 72 TP53 polymorphism which reduces p53 apoptotic activity. Our studies demonstrated a higher prevalence of HHV type 6 in patients submitted to renal transplants than in a control population, suggesting that TP53 gene polymorphisms might affect the susceptibility to HHV infection. In addition, we observed that HHV can increase the risk of skin cancer, an event associated with the Glutathione S-Trans ferase (GST) genotypic profile GSTM1-GSTT1+. More recently, while investigating autoimmune diseases, we observed a high prevalence of HHV type 7, but not type 6 infection in Graves' disease patients. These individuals also presented the codon 72 TP53 germline polymorphism more frequently. Although further studies are needed, our results suggest that viral agents such as HHV may trigger autoimmune as well as neoplastic diseases in individuals with a predisposing genetic profile.17323023

Role of glutathione-S-transferase and codon 72 of P53 genotypes in epithelial ovarian cancer patients

Purpose . A series of polymorphisms in germ-line DNA have been investigated in an effort to delineate polygenic models of cancer susceptibility and prognosis. As low-penetrance susceptibility genes may combine additively or multiplicatively and contribute to cancer incidence and to the response to chemotherapy, we studied GSTT1, GSTM1, GSTO2, GSTP1 and codon 72 of p53 genotype profiles in ovarian cancer patients. Methods . We compared 69 ovarian cancer patients with 222 control healthy women paired for ethnic and life-style characteristics. Outcome was evaluated in 29 stage III and IV patients submitted to a platinum-based chemotherapy followed-up for 6-29 months (17 +/- 9 months). Results . GSTT1, GSTM1, GSTO2 and GSTP1 genes presented a similar genotype distribution, but codon 72 of p53 gene wild-type variant was less frequent in ovarian cancer patients than in controls (chi(2); P = 0.0004). Conclusions. We were unable to demonstrate any association between the GST genotypes studied and the risk of ovarian cancer but the inheritance of a heterozygous Arg/Pro genotype of p53 increased the risk of ovarian cancer more than 2.5 times (OR = 2.571; 95% CI = 1.453-4.550). There was no association of the studied genes to any clinical or pathological feature of the patients or to their response to chemotherapy.132852152

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

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)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. Design This study was developed in University of Campinas (Unicamp). Patients We studied 132 patients with HMTC, 88 first-degree relatives of HMTC patients and 575 control individuals. Measurements All patients with MTC and their relatives were sequenced for the RET gene and five genes were genotyped using TaqMan (R) system. Results We observed that the inheritance of CYP1A2*F (OR = 2.10; 95% CI = 1.11-3.97; P = 0.022), GSTP1 (OR = 4.41; 95% CI = 2.47-7.88; P < 0.001) and NAT2 (OR = 2.54; 95% CI = 1.16-5.58; P = 0.020) variants increased the risk for HMTC. In addition, multiple regression analysis showed that the inheritance of GSTP1 polymorphisms was associated with the diagnosis in older patients (B = 8.0229; 95% IC = +/- 5.5735; P = 0.0054). Concerning the group of HTMC relatives, CYP1A2*F (OR = 2: 40; 95% CI = 1.19-4.86; P = 0.015), CYP1A1 m1 (OR = 2.79; 95% CI = 1: 04-7.51; P = 0.042), GSTP1 (OR = 2.86; 95% IC = 1.53-5.32; P < 0.001) and NAT2 (OR = 2.25; 95% IC = 1.20-4.22; P = 0.012) were associated with HMTC risk. Conclusions We have demonstrated that the inheritance of specific genes determining the individual response to environmental toxins may contribute to the risk and phenotypic variability that exists in patients with HMTC. Moreover, we identified a group at risk in relatives of HMTC patients.792288293Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [07 067-5

Role of the N-Acetyltransferase 2 Detoxification System in Thyroid Cancer Susceptibility

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)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.We used PCR-RFLP assays and the combination of 6 variant alleles to define 18 NAT2 haplotypes that characterized slow, intermediate, or rapid phenotypes. Results: A multivariate logistic regression analysis identified the presence of *12A and the absence of *12B, *13, *14B, *14D, *6A, and *7A NAT2 haplotypes as risk factors for DTC. The inheritance of a rapid acetylation phenotype doubled the risk for a papillary carcinoma (odds ratio, 2.024; 95% confidence interval, 1.252-3.272).We found no relationship between genotypes and clinical, pathologic, or laboratory features of patients or between genotypes and outcome. Conclusions: We showed that NAT2 genotypes and the NAT2 rapid acetylation phenotype are important susceptibility factors for DTC, suggesting that NAT2 detoxification system is involved in this tumor pathogenesis.151406412Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)National Council for Scientific and Technological Development [470317/2006-0]Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)FAPESP [0601651-1]National Council for Scientific and Technological Development [470317/2006-0

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. We aimed to assess the influence of the GST, CYP and TP53 gene polymorphisms in the risk of Graves' disease and its outcome. Design Prospective case-control study. Patients A PCR-based strategy was used for GSTT1, GSTM1, GSTP1, CYP1A1 and TP53 codon 72 genotypes in a group of 400 Graves' disease patients, and to compare them to 574 control individuals with similar environmental exposure features. Results GSTM1 and GSTT1 genotypes were equally distributed in cases and controls, repectively. However, GSTP1 (P < 0.0001), CYP1A1 (P < 0.0033) and Pro/ProTP53 (P < 0.0035) variants appeared more frequently in Graves' disease patients than in controls. A multivariate analysis indicated that cigarette smoking and inheritance of GSTP1, CYP1A1 and Pro/ProTP53 variants were important risk factors for Graves' disease, but only smoking appeared as an independent risk factor for Graves' ophthalmopathy. There was no association between clinical features, including ophthalmopathy or treatment outcome, and the studied genotypes. Conclusion We concluded that GSTP1, CYP1A1 and TP53, but not GSTT1 and GSTM1 germline polymorphisms, may be associated with smoking-related Graves' disease susceptibility and configure a risk profile for the disease. However, these polymorphisms do not influence the patients' response to treatment.68698298

Identifying a risk profile for thyroid cancer

The large use of simple and effective diagnostic tools has significantly contributed to the increase in diagnosis of thyroid cancer over the past years. However, there is compelling evidence that most micropapillary carcinomas have an indolent behavior and may never evolve into clinical cancers. Therefore, there is an urgent need for new tools able to predict which thyroid cancers will remain silent, and which thyroid cancers will present an aggressive behavior. There are a number of well-established clinical predictors of malignancy and recent studies have suggested that some of the patient's laboratory data and image methods may be useful. Molecular markers have also been increasingly tested and some of them appear to be very promising, such as BRAF, a few GST genes and p53 polymorphisms. In addition, modern tools, such as immunocytochemical markers, and the measure of the fractal nature of chromatin organization may increase the specificity of the pathological diagnosis of malignancy and help ascertain the prognosis. Guidelines designed to select nodules for further evaluation, as well as new methods aimed at distinguishing carcinomas of higher aggressiveness among the usually indolent thyroid tumors are an utmost necessity.51571372