Nitrosamines and oesophageal cancer. A study of factors influencing the distribution and metabolism of nitrosamines and the enzymes responsible for their activation

Nitrosamines produce cancer in most species and possess remarkable organ specificity. Because they are the only carcinogens which can produce oesophageal tumours in experimental animals, and because all humans are exposed to them, it has been suggested that they produce oesophageal cancer in man. The organotropism of nitrosamines depends largely on the distribution of the nitrosamine and the P450s capable of metabolizing it in the animal body. Ethanol consumption, the main factor associated with oesophageal cancer in the West, changes the pharmacokinetics of nitrosamines, increasing the damage to extrahepatic organs, in particular to the oesophagus, and it has been suggested that these changes are responsible for the effect of ethanol on human oesophageal cancer. The influence of two factors associated with a high incidence of oesophageal cancer, opium (and morphine the major alkaloid found in opium), and isoamyl alcohol, a contaminant of Calvados, on the pharmacokinetics of N-nitrosodimethylamine and N- nitrosodiethylamine was investigated through measurement of their influence on the organ to organ distribution of alkylation produced by these nitrosamines, inhibition of the metabolism of these nitrosamines in vitro, and with isoamyl alcohol, its influence on reactions metabolized by different P450s. Morphine and opium dramatically change the pharmacokinetics of NDMA and NDEA, with inhibition of first pass clearance of NDMA and a shift of the metabolism of NDEA from the liver to the oesophagus. Although the mechanisms of these changes has have not been completely elucidated, the results are very similar to those previously obtained with ethanol. However, although isoamyl alcohol inhibited the general metabolism of NDEA in the rat, it did not affected its organotropism, and affects a broader range of P450s than ethanol. The oesophageal monooxygenase system was investigated in depth and compared to the liver through administration of chemicals which induce P450s in the liver, spectrophotometric measurements of the components of the monooxygenase system, western blot analysis of these components and particular forms of P450s, the capacity of oesophageal microsomes to metabolize different compounds, and the influence of nitrosamines on the metabolism of these compounds. The presence of P450 1A1, but not 2E1 or 2B1 and 2B2 in the oesophagus together with evidence that P450 1A1 can participate in the metabolism of N-nitrosomethylbenzylamine, the most powerful oesophageal carcinogen in the rat, is suggested to be one of the factors contributing to the organotropism of some nitrosamines for that organ

Lower lip squamous cell carcinoma in patients with photosensitive disorders : analysis of cases treated at the Brazilian National Cancer Institute (INCA) from 1999 to 2012

Lower lip squamous cell carcinoma (LLSCC) is a common malignancy of the head and neck, being mainly a consequence of a chronic exposure to ultraviolet (UV) light solar radiation. Here, we evaluated the clinicopathological profile of patients with photosensitive disorders (xeroderma pigmentosum, lupus erythematosus and albinism) that developed LLSCC. Data from patients who had a diagnosed LLSCC with a prior xeroderma pigmentosum, lupus erythematosus or albinism diagnosis that were treated at INCA from 1999 to 2012 were collected from patients? medical records (n=16). The control group was composed of 68 patients with LLSCC without a medical history of photosensitivity. The clinicopathological data of this study population were collected and the association between these variables was analyzed by Fisher?s exact test. Survival curves were constructed using the Kaplan?Meier method and compared by log-rank test. All statistical analyses were performed using SPSS statistics package. The mean age of patients in the photosensitive and non-photosensitive groups was 42 years and 67 years, respectively (p<0.0001). A previous history of malignant diseases was more common in the photosensitive group (p=0.001). In both groups, most tumors showed a pathological stage I/II disease. Overall and cancer-specific survival were not statistically different. However, disease-free interval showed a significant difference (p=0.01) between the photosensitive and non-photosensitive patients. Photosensitive patients presented LLSCC at earlier age but it usually was not the primary tumor in these patients. Furthermore, a more aggressive pathological behavior was not seen when compared with tumors from non-photosensitive patients. The disease-free interval was lower in photosensitive patients, as expected

Multidrug resistance 1 gene polymorphisms may determine Crohn's disease behavior in patients from Rio de Janeiro

OBJECTIVES: Conflicting data from studies on the potential role of multidrug resistance 1 gene polymorphisms in inflammatory bowel disease may result from the analysis of genetically and geographically distinct populations. Here, we investigated whether multidrug resistance 1 gene polymorphisms are associated with inflammatory bowel diseases in patients from Rio de Janeiro. METHODS: We analyzed 123 Crohn's disease patients and 83 ulcerative colitis patients to determine the presence of the multidrug resistance 1 gene polymorphisms C1236T, G2677T and C3435T. In particular, the genotype frequencies of Crohn's disease and ulcerative colitis patients were analyzed. Genotype-phenotype associations with major clinical characteristics were established, and estimated risks were calculated for the mutations. RESULTS: No significant difference was observed in the genotype frequencies of the multidrug resistance 1 G2677T/A and C3435T polymorphisms between Crohn's disease and ulcerative colitis patients. In contrast, the C1236T polymorphism was significantly more common in Crohn's disease than in ulcerative colitis (p = 0.047). A significant association was also found between the multidrug resistance 1 C3435T polymorphism and the stricturing form of Crohn's disease (OR: 4.13; p = 0.009), whereas no association was found with penetrating behavior (OR: 0.33; p = 0.094). In Crohn's disease, a positive association was also found between the C3435T polymorphism and corticosteroid resistance/refractoriness (OR: 4.14; p = 0.010). However, no significant association was found between multidrug resistance 1 gene polymorphisms and UC subphenotypic categories. CONCLUSION: The multidrug resistance 1 gene polymorphism C3435T is associated with the stricturing phenotype and an inappropriate response to therapy in Crohn's disease. This association with Crohn's disease may support additional pathogenic roles for the multidrug resistance 1 gene in regulating gut-microbiota interactions and in mediating fibrosis. Understanding the effects of several drugs associated with multidrug resistance 1 gene variants may aid in the selection of customized therapeutic regimens

Upper aerodigestive tract squamous cell carcinomas show distinct overall DNA methylation profiles and different molecular mechanisms behind WNT signaling disruption

SIMPLE SUMMARY: Squamous cell carcinomas of the upper aerodigestive tract are highly incident, lethal, and share the same epithelial lining of origin, risk factors and genetic alterations. However, their biological and clinical behaviors differ, having an impact on patient survival. This study aimed at identifying the main DNA methylation differences between these tumors, giving an overview of the main genomic regions affected, whether DNA methylation gains or losses are more common, the impact on gene expression and the signaling pathways affected. This knowledge will help identifying potential site-specific biomarkers as well as shedding light on whether epigenetic mechanisms explain, at least in part, the diverse behavior of upper aerodigestive tract tumors. ABSTRACT: Upper aerodigestive tract (UADT) tumors present different biological behavior and prognosis, suggesting specific molecular mechanisms underlying their development. However, they are rarely considered as single entities (particularly head and neck subsites) and share the most common genetic alterations. Therefore, there is a need for a better understanding of the global DNA methylation differences among UADT tumors. We performed a genome-wide DNA methylation analysis of esophageal (ESCC), laryngeal (LSCC), oral (OSCC) and oropharyngeal (OPSCC) squamous cell carcinomas, and their non-tumor counterparts. The unsupervised analysis showed that non-tumor tissues present markedly distinct DNA methylation profiles, while tumors are highly heterogeneous. Hypomethylation was more frequent in LSCC and OPSCC, while ESCC and OSCC presented mostly hypermethylation, with the latter showing a CpG island overrepresentation. Differentially methylated regions affected genes in 127 signaling pathways, with only 3.1% of these being common among different tumor subsites, but with different genes affected. The WNT signaling pathway, known to be dysregulated in different epithelial tumors, is a frequent hit for DNA methylation and gene expression alterations in ESCC and OPSCC, but mostly for genetic alterations in LSCC and OSCC. UADT tumor subsites present differences in genome-wide methylation regarding their profile, intensity, genomic regions and signaling pathways affected

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UNIPAMPA SÃO GABRIE

DNA methylation changes associated with risk factors in tumors of the upper aerodigestive tract

Cancers of the upper aerodigestive tract (UADT) are common forms of malignancy associated with tobacco and alcohol exposures, although human papillomavirus and nutritional deficiency are also important risk factors. While somatically acquired DNA methylation changes have been associated with UADT cancers, what triggers these events and precise epigenetic targets are poorly understood. In this study, we applied quantitative profiling of DNA methylation states in a panel of cancer-associated genes to a case-control study of UADT cancers. Our analyses revealed a high frequency of aberrant hypermethylation of several genes, including MYOD1, CHRNA3 and MTHFR in UADT tumors, whereas CDKN2A was moderately hypermethylated. Among differentially methylated genes, we identified a new gene (the nicotinic acetycholine receptor gene) as target of aberrant hypermethylation in UADT cancers, suggesting that epigenetic deregulation of nicotinic acetycholine receptors in non-neuronal tissues may promote the development of UADT cancers. Importantly, we found that sex and age is strongly associated with the methylation states, whereas tobacco smoking and alcohol intake may also influence the methylation levels in specific genes. This study identifies aberrant DNA methylation patterns in UADT cancers and suggests a potential mechanism by which environmental factors may deregulate key cellular genes involved in tumor suppression and contribute to UADT cancers.IARCIARCla Ligue National (Francaise) Contre le Cancerla Ligue National (Francaise) Contre le CancerNational Institutes of Health/National Cancer Institute (NIH/NCI), United StatesNational Institutes of Health/National Cancer Institute (NIH/NCI), United StatesAssociation pour la Recherche sur le Cancer (ARC, France)l'Association pour la Recherche sur le Cancer (ARC), Francela Ligue Nationale (Francaise) Contre le Cancer (Comite SaoneetLoire), Francela Ligue Nationale (Francaise) Contre le Cancer (Comite Saone-et-Loire), FranceSwiss Bridge AwardSwiss Bridge Awar

Predictors of Survival After Head and Neck Squamous Cell Carcinoma in South America: The InterCHANGE Study.

PURPOSE: Head and neck squamous cell carcinoma (HNSCC) incidence is high in South America, where recent data on survival are sparse. We investigated the main predictors of HNSCC survival in Brazil, Argentina, Uruguay, and Colombia. METHODS: Sociodemographic and lifestyle information was obtained from standardized interviews, and clinicopathologic data were extracted from medical records and pathologic reports. The Kaplan-Meier method and Cox regression were used for statistical analyses. RESULTS: Of 1,463 patients, 378 had a larynx cancer (LC), 78 hypopharynx cancer (HC), 599 oral cavity cancer (OC), and 408 oropharynx cancer (OPC). Most patients (55.5%) were diagnosed with stage IV disease, ranging from 47.6% for LC to 70.8% for OPC. Three-year survival rates were 56.0% for LC, 54.7% for OC, 48.0% for OPC, and 37.8% for HC. In multivariable models, patients with stage IV disease had approximately 7.6 (LC/HC), 11.7 (OC), and 3.5 (OPC) times higher mortality than patients with stage I disease. Current and former drinkers with LC or HC had approximately 2 times higher mortality than never-drinkers. In addition, older age at diagnosis was independently associated with worse survival for all sites. In a subset analysis of 198 patients with OPC with available human papillomavirus (HPV) type 16 data, those with HPV-unrelated OPC had a significantly worse 3-year survival compared with those with HPV-related OPC (44.6% v 75.6%, respectively), corresponding to a 3.4 times higher mortality. CONCLUSION: Late stage at diagnosis was the strongest predictor of lower HNSCC survival. Early cancer detection and reduction of harmful alcohol use are fundamental to decrease the high burden of HNSCC in South America