Jacqueline Miranda de Lima

DNA methylation as an epigenetic biomarker in colorectal cancer.

Sporadic colorectal cancer (CRC) is a consequence of the accumulation of genetic and epigenetic alterations that result in the transformation of normal colonic epithelial cells to adenocarcinomas. Studies have indicated that a common event in the tumorigenesis of CRC is the association of global hypomethylation with discrete hypermethylation at the promoter regions of specific genes that are involved in cell cycle regulation, DNA repair, apoptosis, angiogenesis, adhesion and invasion. The present study aimed to investigate the epigenetic changes (DNA methylation) in 24 candidate genes in CRC. A total of 10 candidate hypermethylated (HM) and unmethylated (UM) genes were identified that may be useful epigenetic markers for non-invasive CRC screening. The five genes that had the highest average UM percentages in the control group were MLH1 (71.7%), DKK2 (69.6%), CDKN2A (68.4%), APC (67.5%) and hsa-mir-342 (67.4%). RUNX3 (58.9%), PCDH10 (55.5%), SFRP5 (52.1%), IGF2 (50.4%) and Hnf1b (50.0%) were the five genes with the highest average HM percentages in the test group. In summary, the present preliminary study identified the methylation profiles of normal and cancerous colonic epithelial tissues, and provided the groundwork for future large-scale methylation studies.

E-cadherin and metalloproteinase-1 and -7 polymorphisms in colorectal cancer

PURPOSE E-cadherin (CDH1) and metalloproteinase (MMP) polymorphisms could play a crucial role in cancer invasion. Our aim was to investigate the influence of the -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 polymorphisms on the frequency and progression of colorectal cancer (CRC). EXPERIMENTAL DESIGN A total of 130 patients with CRC and 130 noncancer controls were studied. The -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 genotypes were analyzed by polymerase chain reaction-restriction fragment length polymorphism. RESULTS Patients with the 1G allele and a family history of CRC showed a six times higher risk of developing CRC (OR: 6.45, 95% CI: 2.02-20.6, p=0.001). The A/A CDH1 genotype was associated with a higher risk of metastatic disease (OR: 3.43, 95% CI: 1.27-9.27, p=0.023). A higher marginal risk of metastatic disease was observed for MMP-1 genotypes 1G/1G and 1G/2G (OR: 2.97, 95% CI: 0.93-9.47, p=0.098). CONCLUSIONS The -160C/A CDH1, -1607ins/delG MMP-1 and -181A/G MMP-7 single nucleotide polymorphisms did not modify the risk of CRC development. Patients with the 1G/1G or 1G/2G genotype and a family history of CRC presented a higher risk of CRC. The AA CDH1 and 1G/1G and 1G/2G MMP-1 genotypes might be associated with advanced metastatic disease, but are not markers of lymphatic metastasis.

N-Acetyltransferase 2 genetic polymorphisms and risk of colorectal cancer

AIM To investigate the possible association between meat intake, cigarette smoking and N-acetyltransferase 2 (NAT2) genetic polymorphisms on colorectal cancer (CRC) risk. METHODS Patients with CRC were matched for gender and age to healthy controls. Meat intake and cigarette smoking were assessed using a specific frequency questionnaire. DNA was extracted from peripheral blood and the genotypes of the polymorphism were assessed by polymerase chain reaction-restriction fragment length polymorphism. Five NAT2 alleles were studied (WT, M1, M2, M3 and M4) using specific digestion enzymes. RESULTS A total of 147 patients with colorectal cancer (76 women and 90 men with colon cancer) and 212 controls were studied. The mean age of the two groups was 62 years. More than half the subjects (59.8% in the case group and 51.9% in the control group) were NAT2 slow acetylators. The odds ratio for colorectal cancer was 1.38 (95% CI: 0.90-2.12) in slow acetylators. Although the number of women was small (n = 76 in the case group), the cancer risk was found to be lower in intermediate (W/Mx) acetylators [odds ratio (OR): 0.55, 95% confidence interval (95% CI): 0.29-1.02]. This difference was not observed in men (OR: 0.56, 95% CI: 0.16-2.00). Among NAT2 fast acetylators (W/W or W/Mx), meat consumption more than 3 times a week increased the risk of colorectal cancer (OR: 2.05, 95% CI: 1.01-4.16). In contrast, cigarette smoking increased the risk of CRC among slow acetylators (OR: 1.97, 95% CI: 1.02-3.79). CONCLUSION The risk of CRC was higher among fast acetylators who reported a higher meat intake. Slow NAT2 acetylation was associated with an increased risk of CRC.

Estudo do polimorfismo genético no gene p53 (códon 72) em câncer colorretal

BACKGROUND: Polymorphisms are genetic variations that can occur in sequences of codons, leading to defective proteins. p53 is the most commonly gene affected in human cancer. The polymorphism of this gene occurs by a substitution of a base in codon 72 and may increase the risk of cancer. AIM: To investigate the possible association between p53 arginine/72 proline polymorphism and susceptibility to colorectal cancer. PATIENTS AND METHODS: This polymorphism was studied by polymerization chain reaction using specific primers in 100 patients with colorectal cancer paired by sex and age to 100 patients without cancer. Alcohol and tobacco used by all the patients and clinical aspects as stage, grade of differentiation and recurrence in the case group was compared with the genotype analyzed. RESULTS: The frequency of homozygosis for arginine was 56% in the cancer group and 58% in the control group. No significant difference was observed among both groups. This genotype was more frequent in colorectal cancer patients stage IV than in stage I (80% versus 14%). There was no significant difference between genotypes and alcohol, tobacco, grade of differentiation or recurrence. CONCLUSION: Homozygosity for arginine was the most prevalent genotype in both groups. The frequency of codon 72 proline/arginine p53 gene polymorphism was not correlated with a higher risk of colorectal cancer. Arginine/arginine genotype was more prevalent in advanced cancer patients (stage IV).

P53 Arg72Pro polymorphism in gastric cancer patients.

INTRODUCTION Polymorphism in codon 72, exon 4 of p53 may alter apoptosis and cancer progression. PATIENTS AND METHODS P53 Arg72Pro genotype was assessed by PCR from 84 gastric cancer patients and 185 controls. The control group was comparable in sex, race, age, smoking, and alcohol intake to the cancer group. RESULTS AND DISCUSSION There was no difference among the frequency of the alleles or genotypes between the groups. P53 Pro/Pro was associated to a lower risk of metastatic disease (p = 0.02) but not to lymph nodes metastasis or worst prognosis. Arg/Arg or Arg/Pro genotype may be associated to metastatic disease.

Variação de peso, grau de escolaridade, saneamento básico, etilismo, tabagismo e hábito alimentar pregresso em pacientes com cancêr de estômago

BACKGROUND About 35% of the cancer patients are involved in factors coming from the diet and others like alcohol, smoking, sunlight, chemical agents and infections caused by virus. The stomach cancer is the second cause of cancer in the world with 9.9 % of all diagnosis and about 12.1 % of death cases. AIMS Evaluate the body weight, educational achievement, basic sanitation, smoking, alcoholism and eating habit among patients with gastric cancer and a control group. METHODS Seventy patients with gastric cancer were paired with 70 subjects without cancer. Data on the weight and height, educational attainment, basic sanitation, smoking, alcoholism and eating habits of the patients were collected from the clinical records and from interviews. RESULTS Forty two patients were men, the mean age were 60 years old. The actual weight and body mass index of the patients were smaller when compared to the controls. Within the group of patients with gastric cancer, 21 never attended school, and for those who attended, 55% did not finish the elementary school. Among the patient group, 32.9% of them lived in housing with basic sanitation and 37.1% with electricity, against 68.6% of the controls, and 58.6% of the patients lived in rural area, against only 7.1% of the controls. Among the test group, 65.7% of the patients were smokers, whereas in the control group, 44.3% were smokers. In addition, there was also difference in the duration of smoking habit. Alcoholism was also more frequent in the cancer group (44% vs 19%). Food rich in salt, condiments, nitrates, saturated fat, complex carbohydrates, refined sugar and fried salted food had been more used by gastric cancer patients. CONCLUSION The patients with gastric cancer presented with: less weight, low quality of life as indicated by lower or no access to basic sanitation, electricity and schooling, lived predominantly in rural area, high incidence of alcohol intake and higher intake of high fat foods and industrialized foods.

-765 G>C polymorphism of the cox-2 gene and gastric cancer risk in brazilian population

CONTEXT Genomic alterations play important roles in gastric cancer carcinogenesis. Cyclooxygenases (COX) are important enzymes in the maintenance of mucosal integrity and in pathological processes, mainly in inflammation and cancer. The -765G>C COX-2 polymorphism has been implicated in gastric cancer risk. OBJECTIVES To evaluate the COX-2 gene polymorphism as a predictor of gastric cancer risk. METHODS One hundred gastric cancer patients and 150 controls were enrolled from a Brazilian centre. Personal data regarding related risk factors, including alcohol consumption and smoking behavior, were collected via questionnaire. DNA was extracted from peripheral blood and the genotypes were analyzed using PCR-restriction fragment length polymorphism. RESULTS G/G, G/C and C/C genotypes frequencies was 42.7%, 50% and 7.3%, respectively in controls and 59.0%, 34.0% and 7.0% in gastric cancer. The frequency of the genotypes differed between the groups (P = 0.033). A higher risk of gastric cancer was associated with COX-2 -765G/G genotype (P = 0.048; OR:1.98, 95% CI = 1.01-3.90). Alcohol consumption and smoking in patients with -765G/G genotype also increased the risk of gastric cancer. CONCLUSIONS The -765G/G genotype and the -765G allele had been associated with an increased risk for gastric cancer. The presence of smoking and alcohol consumption increased the risk for gastric cancer in subjects with -765G/G genotype compared with the control group. Polymorphism of COX-2 gene and gastric cancer risk.

Study of the polymorphisms of cyclooxygenase-2 (-765G>C) and 5-lipoxygenase (1708G>A) in patients with colorectal cancer.

Colorectal cancer (CRC) is the fourth most common cause of cancer-related mortality worldwide. Genetic alterations have been associated with an increased risk of cancer and greater tumor aggressiveness. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) genes are important in cell cycle regulation, tumor growth and prostaglandin synthesis. The aim of the present study was to investigate the association between polymorphisms in the COX-2 and 5-LOX genes and the risk of CRC. A case-control study was conducted in patients with CRC matched for gender and age to a control group. DNA was extracted from peripheral leukocytes, and the polymorphisms were analyzed by polymerase chain reaction-restriction fragment length polymorphism and gene sequencing. A specific questionnaire was applied to evaluate smoking, excessive alcohol consumption, physical activity, non-steroidal anti-inflammatory drug use and meat, fiber and fat intake. A total of 185 patients with CRC and 146 controls were studied. The heterozygous GC genotype of the COX-2 gene polymorphism was the most common in the two groups (60.0% in CRC patients and 52.7% in controls). The CC genotype was associated with an increased risk of CRC (odds ratio, 3.63; 95% confidence interval, 1.31–10.1; P=0.013). The homozygous wild-type genotype of the 5-LOX gene polymorphism was detected in 72.4% of the CRC patients and in 71.2% of the control subjects. The homozygous mutant genotype (CC) of the COX-2 gene is an independent risk factor for CRC. No association was found between 5-LOX genotypes and CRC.