ABSTRACT
MTAP is a ubiquitously expressed gene important for adenine and methionine salvage. The gene is located at 9p21, a chromosome region often deleted in breast carcinomas, similar to CDKN2A, a recognized tumor suppressor gene. Several research groups have shown that MTAP acts as a tumor suppressor, and some therapeutic approaches were proposed based on a tumors´ MTAP status. We analyzed MTAP and CDKN2A gene (RT-qPCR) and protein (western-blotting) expression in seven breast cancer cell lines and evaluated their promoter methylation patterns to better characterize the contribution of these genes to breast cancer. Cytotoxicity assays with inhibitors of de novo adenine synthesis (5-FU, AZA and MTX) after MTAP gene knockdown showed an increased sensitivity, mainly to 5-FU. MTAP expression was also evaluated in two groups of samples from breast cancer patients, fresh tumors and paired normal breast tissue, and from formalin-fixed paraffin embedded (FFPE) core breast cancer samples diagnosed as Luminal-A tumors and triple negative breast tumors (TNBC). The difference of MTAP expression between fresh tumors and normal tissues was not statistically significant. However, MTAP expression was significantly higher in Luminal-A breast tumors than in TNBC, suggesting the lack of expression in more aggressive breast tumors and the possibility of using the new approaches based on MTAP status in TNBC.
Subject(s)
Adenocarcinoma, Mucinous/genetics , Carcinoma, Ductal, Breast/genetics , Carcinoma, Lobular/genetics , Cyclin-Dependent Kinase Inhibitor p16/genetics , Gene Expression Regulation, Neoplastic , Purine-Nucleoside Phosphorylase/genetics , Triple Negative Breast Neoplasms/genetics , Adenocarcinoma, Mucinous/drug therapy , Adenocarcinoma, Mucinous/metabolism , Adenocarcinoma, Mucinous/pathology , Antineoplastic Agents/pharmacology , Azacitidine/pharmacology , Carcinoma, Ductal, Breast/drug therapy , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/drug therapy , Carcinoma, Lobular/metabolism , Carcinoma, Lobular/pathology , Cell Line, Tumor , Cyclin-Dependent Kinase Inhibitor p16/metabolism , DNA Methylation , Estrogen Receptor alpha/deficiency , Estrogen Receptor alpha/genetics , Female , Fluorouracil/pharmacology , Humans , Lymphatic Metastasis , Methotrexate/pharmacology , Organ Specificity , Promoter Regions, Genetic , Purine-Nucleoside Phosphorylase/antagonists & inhibitors , Purine-Nucleoside Phosphorylase/metabolism , RNA, Small Interfering/genetics , RNA, Small Interfering/metabolism , Receptor, ErbB-2/deficiency , Receptor, ErbB-2/genetics , Receptors, Progesterone/deficiency , Receptors, Progesterone/genetics , Signal Transduction , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/metabolism , Triple Negative Breast Neoplasms/pathologyABSTRACT
Oral carcinoma is the sixth most frequent type of cancer in the world and the seventh most common in Brazil (the country with the highest incidence in Latin America). Mean five-year survival remains one of the lowest among the main cancers, thus justifying studies that contribute to the development of preventive strategies. The aim of this study was to compare the epidemiological, clinical, and histological characteristics of 91 patients with oral carcinoma. Mean age was 58.62 +/- 10.46 years, and male-to-female ratio was 6.6:1.0 (79 men and 12 women). European descendants predominated with 79 patients (86.8%). Eighty-five individuals (93.4%) smoked and 70 (76.9%) consumed alcohol regularly. Anatomical distribution of tumors was: 27 (29.7%) tongue; 18 (19.8%) floor of mouth; 11 (12.1%) oropharynx; and 11 (12.1%) oral mucosa. Fifty-seven patients (62.6%) presented lymph node involvement and three (3.3%) had distant metastases. Surgery and radiotherapy were used in 43.2% of patients. With the exception of the male/female ratio (which was higher), our data are consistent with previous studies on oral carcinoma patients.
Subject(s)
Carcinoma, Squamous Cell/epidemiology , Mouth Neoplasms/epidemiology , Brazil/epidemiology , Female , Humans , Incidence , Male , Middle Aged , Risk Factors , Sex Distribution , Smoking/adverse effectsABSTRACT
Oral carcinoma is the sixth most frequent type of cancer in the world and the seventh most common in Brazil (the country with the highest incidence in Latin America). Mean five-year survival remains one of the lowest among the main cancers, thus justifying studies that contribute to the development of preventive strategies. The aim of this study was to compare the epidemiological, clinical, and histological characteristics of 91 patients with oral carcinoma. Mean age was 58.62 ± 10.46 years, and male-to-female ratio was 6.6:1.0 (79 men and 12 women). European descendants predominated with 79 patients (86.8 percent). Eighty-five individuals (93.4 percent) smoked and 70 (76.9 percent) consumed alcohol regularly. Anatomical distribution of tumors was: 27 (29.7 percent) tongue; 18 (19.8 percent) floor of mouth; 11 (12.1 percent) oropharynx; and 11 (12.1 percent) oral mucosa. Fifty-seven patients (62.6 percent) presented lymph node involvement and three (3.3 percent) had distant metastases. Surgery and radiotherapy were used in 43.2 percent of patients. With the exception of the male/female ratio (which was higher), our data are consistent with previous studies on oral carcinoma patients.
O carcinoma bucal é o sexto tipo mais comum de câncer no mundo e o sétimo no Brasil, onde ocorre a maior incidência da América Latina. A sobrevida média de aproximadamente cinco anos permanece como uma das menores entre os principais cânceres, justificando estudos que auxiliem no delineamento de estratégias de prevenção. Este estudo objetivou avaliar em uma amostra de 91 pacientes portadores de carcinomas bucais características epidemiológicas; fatores de risco, clínicos e histopatológicos. A média de idade foi de 58,62 ± 10,46 anos e a razão sexual de 6,6:1,0 (79 homens e 12 mulheres). A etnia euro-descendente foi predominante com 79 (86,8 por cento) pacientes. Oitenta e cinco (93,4 por cento) indivíduos eram tabagistas e 70 (76,9 por cento) etilistas. As localizações anatômicas prevalentes foram: 27 tumores (29,7 por cento) de língua; 18 (19,8 por cento) de assoalho; 11(12,1 por cento) de orofaringe e 11 (12,1 por cento) de mucosa. Cinqüenta e sete (62,6 por cento) pacientes apresentaram os linfonodos comprometidos e três apresentaram (3,3 por cento) metástases à distância. A maioria dos pacientes (43,2 por cento) recebeu tratamento cirúrgico e radioterápico. Com exceção da proporção sexual, nossos dados concordam com os freqüentemente descritos para portadores de carcinomas bucais.
Subject(s)
Female , Humans , Male , Middle Aged , Carcinoma, Squamous Cell/epidemiology , Mouth Neoplasms/epidemiology , Brazil/epidemiology , Incidence , Risk Factors , Sex Distribution , Smoking/adverse effectsABSTRACT
Individual variability in xenobiotic metabolism has been associated with susceptibility to developing complex diseases. Genes involved in xenobiotic metabolism have been evaluated in association studies; the difficulty of obtaining accurate gene frequencies in mixed populations makes interpretation of the results difficult. We sought to estimate population parameters for the cytochrome P450 and glutathione S-transferase gene families, thus contributing to studies using these genes as markers. We describe the frequencies of six genes (CYP1A1, CYP2D6, CYP2E1, GSTM1, GSTT1, and GSTP1) and estimate population parameters in 115 Euro-descendants and 196 Afro-descendants from Curitiba, South of Brazil. PCR-based methods were used for genotyping, and statistical analysis were performed by AMOVA with ARLEQUIN software. The mutant allele frequencies in the Afro-descendants and Euro-descendants, respectively, were: CYP1A1*2A = 30.1% and 15.2%; CYP2D6*4 = 14.5% and 21.5%; CYP2E1*5B = 7.9% and 5%; GSTP1*B = 37.8% and 28.3%. The null genotype frequencies were: GSTM1*0 = 36.8% and 46.1%; GSTT1*0 = 24.2% and 17.4%.
ABSTRACT
Individual variability in xenobiotic metabolism has been associated with susceptibility to developing complex diseases. Genes involved in xenobiotic metabolism have been evaluated in association studies; the difficulty of obtaining accurate gene frequencies in mixed populations makes interpretation of the results difficult. We sought to estimate population parameters for the cytochrome P450 and glutathione S-transferase gene families, thus contributing to studies using these genes as markers. We describe the frequencies of six genes (CYP1A1, CYP2D6, CYP2E1, GSTM1, GSTT1, and GSTP1) and estimate population parameters in 115 Euro-descendants and 196 Afro-descendants from Curitiba, South of Brazil. PCR-based methods were used for genotyping, and statistical analysis were performed by AMOVA with ARLEQUIN software. The mutant allele frequencies in the Afro-descendants and Euro-descendants, respectively, were: CYP1A1*2A = 30.1 percent and 15.2 percent; CYP2D6*4 = 14.5 percent and 21.5 percent; CYP2E1*5B = 7.9 percent and 5 percent; GSTP1*B = 37.8 percent and 28.3 percent. The null genotype frequencies were: GSTM1*0 = 36.8 percent and 46.1 percent; GSTT1*0 = 24.2 percent and 17.4 percent.