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Carlos Lopes

Publications and source records attributed to Carlos Lopes.

15 recordsLinked to original sources
PubMed2003

Detection of gene promoter hypermethylation in fine needle washings from breast lesions.

PURPOSE: Fine needle aspiration (FNA) is used widely in diagnostic assessment of breast lesions. However, cytomorphological evaluation depends heavily on the proficiency of cytopathologists. Because epigenetic alterations are frequent and specific enough to potentially augment the accuracy of malignant disease detection, we tested whether hypermethylation analysis of a panel of genes would distinguish benign from malignant breast FNA washings. EXPERIMENTAL DESIGN: FNA washings were collected from 123 female patients harboring suspicious mammary lesions. Sodium bisulfite-modified DNA was amplified by methyl-specific PCR (MSP) for CDH1, GSTP1, BRCA1, and RARbeta to detect gene promoter CpG island methylation. Paired samples of 27 breast cancer tissue and 7 fibroadenomas and 12 samples of normal breast tissue, collected postoperatively, were also analyzed. MSP results were compared with conventional cytomorphological diagnosis. RESULTS: FNAs were cytomorphologically diagnosed as benign (25 cases), malignant (76 cases), suspicious for malignancy (6 cases), and unsatisfactory (16 cases). Percentages of methylated CDH1, GSTP1, BRCA1, and RARbeta in FNA washings were 60, 52, 32, and 16%, and 65.8, 57.9, 39.5, and 34.2% for benign and malignant lesions, respectively. These differences did not reach statistical significance. In all of the paired benign lesions tested, there was absolute concordance. Sixty-seven percent (18 of 27) of FNA washings displayed hypermethylation patterns identical to malignant paired tissue. No methylation was found in the normal breast samples for any of the genes. CONCLUSIONS: Detection of gene hypermethylation in FNA washings by MSP analysis is feasible, but the selected gene panel does not discriminate between benign and malignant breast lesions.

Biopsy, Fine-Needle↗
PubMed2003

Ki-67 index enhances the prognostic accuracy of the urothelial superficial bladder carcinoma risk group classification.

Approximately 80% of bladder tumors are urothelial superficial papillary carcinomas (USPC). Despite a generally good prognosis, these tumors have a strong propensity to recur and about 1/3 of them compared to disease progression. Histological assessment of these superficial tumors is not sufficiently discriminator in predicting prognosis; therefore, we decided to evaluate the prognostic significance of p53 and Ki-67 immunoexpression in low-grade (GI-II) USPC in order to predict the potential outcome of these tumors. P53 and Ki-67 immunoexpression were studied in function of recurrence-free and progression-free survival in 159 primary superficial bladder tumors. A prognostic risk model based on grade, stage and multifocality was also evaluated. P53 accumulation was significantly related to tumor progression (p=0.006). High Ki-67 index (>/=18%) and multifocality were significantly related to recurrence (both p=0.0001) and progression-free survival (both p=0.0001) and were independent prognostic factors in the multivariate analysis. The prognostic risk model based on grade, stage and multifocality was not an efficient discriminator of outcome. Adding the Ki-67 index into the risk model, single pTa/T1-GI Ki-67 positive tumors, usually classified as low risk, were reclassified as of intermediate risk. After this reclassification, the risk group model identified a subgroup of pTa/T1-G1 with a high risk of recurrence and progression. Ki-67 index is a reliable prognostic marker in urothelial superficial bladder carcinoma and, when included into a risk profile classification of the low-grade USPC, the accuracy of the prognostic discrimination is enhanced.

Biomarkers, Tumor↗
PubMed2003

Endothelial nitric oxide synthase gene polymorphisms and the shedding of circulating tumour cells in the blood of prostate cancer patients.

The involvement of endothelial nitric oxide synthase (ecNOS) gene polymorphisms (ecNOS4a/b and Glu-Asp298) on the shedding of tumor cells in the blood of 61 patients with prostate cancer (PCa), was analyzed. Hematogenous micrometastasis with blood circulating tumor cells (CTCs) may be an early event in the natural history of PCa metastization. CTCs can be detected by the presence of messenger RNA prostate specific membrane antigen by reverse transcription-polymerase chain reaction. We found an association between ecNOS4a/b genotypes presenting the a allele (ab/aa) with the presence of CTCs in the blood of PCa under the age of 67 years (P=0.003) and with localized disease (P=0.012). This association was not found for Glu-Asp298 genotypes. In summary, we have identified a nitric oxide related genetic factor associated with micrometastization of prostate cancer. We hypothesize that genotypes with the a allele of the ecNOS4a/b polymorphism may facilitate the survival of CTCs in the blood of cancer patients.

Aged↗
PubMed2003

Platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma: glutathione S-transferase genetic polymorphisms as predictive biomarkers of disease outcome.

BACKGROUND: The glutathione S-transferases (GSTs) are a group of multifunctional enzymes that catalyze the conjugation of glutathione with a variety of electrophilic compounds, including cytotoxic agents. A significant percentage of normal individuals exhibit genetic polymorphism with a homozygous deletion (null genotype) of the genes, leading to absence of the enzyme. METHODS: In the present study we analyzed GSTM1 and GSTT1 polymorphisms in the genomic DNA isolated from peripheral blood of patients with ovarian cancer treated with chemotherapy (paclitaxel and cisplatinum) after cytoreductive surgery and assessed its correlation with the clinical outcome of these patients. The median follow-up for the patients was 30 months. RESULTS: The estimated 3-year survival rate was 59.8% for all patients and 20.8% for carriers of GSTM1-wt/GSTT1-wt (wt indicates wild type) genotype combination (37.7% for GSTM1-wt alone) compared with 83.1% for non-GSTM1-wt/GSTT1-wt genotype carriers (100% for GSTM1-null). The mean survival time was significantly better in patients who are carriers of the GSTM1-null genotype (40.5 vs. 33.5; P=0.006) or carriers of non-GSTM1-wt/ GSTT1-wt genotypes (55.4 vs. 30.7; P=0.009). The progression-free interval was more favorable for GSTM1-null carriers (41.9 vs. 27.4; P=0.024). CONCLUSION: The study suggests that characterization of the drug-metabolizing genetic individual profile can be of great interest in clinical oncology. It can define the optimal chemotherapy for each patient, improve the efficiency, and reduce the incidence of drug toxicity and poor drug responses.

Adenocarcinoma↗
PubMed2003

Karyotypic divergence and convergence in two synchronous lung metastases of a clear cell sarcoma of tendons and aponeuroses with t(12;22)(q13;q12) and type 1 EWS/ATF1.

Clear cell sarcoma of tendons and aponeuroses (CCS) is an uncommon malignancy characterized by a t(12;22)(q13;q12) causing a fusion of the EWS and ATF1 genes. We describe the cytogenetic and molecular genetic analyses of two lung metastases from a CCS patient. Both lesions presented the defining t(12;22) and a type 1 EWS/ATF1 chimeric transcript. The additional cytogenetic changes present in the two lesions allowed us to obtain some insight into the pathogenetic basis of disease progression. Four related clones were identified in the right lung metastasis, permitting a partial reconstitution of the stepwise clonal evolution, whereas the left lung metastasis presented yet another subclone. The comparison of the two karyotypes enabled us to pinpoint which changes occurred in the primary tumor and which emerged independently after the two metastases had been established. We conclude that both clonal divergence and convergence may be operative during tumor progression of CCS.

Adult↗
PubMed2003

Magnification chromoendoscopy for the diagnosis of gastric intestinal metaplasia and dysplasia.

BACKGROUND: The aim of this study was to define the reproducibility and accuracy of magnification chromoendoscopy for the diagnosis of lesions associated with gastric cancer (intestinal metaplasia and dysplasia). METHODS: A total of 136 patients with previously diagnosed lesions and 5 gastrectomy specimens were studied. Endoscopic examination was performed with a magnification endoscope after methylene blue (1%) spraying. According to differences in color and mucosal pattern, groups and subgroups of endoscopic images were defined, and biopsies taken (n = 462). Five endoscopists were asked to classify individually 2 endoscopic images per subgroup on 2 separate occasions. RESULTS: Three groups of endoscopic images were defined: nonmetaplastic, nondysplastic mucosa (I); metaplastic mucosa (II); and dysplastic mucosa (III). Ten subgroups were defined according to pit pattern: round small (IA), round and tubular small (IB), coarse round (IC), and course round pits with a straight pit (ID); blue irregular marks (IIA), blue round and tubular pits (IIB), blue villi (IIC), and blue small pits (IID); and loss of clear pattern, with depression (IIIA) or with slight elevation (IIIB). The kappa statistic for intraobserver agreement on the classification of endoscopic images in groups was 0.86; for interobserver agreement, it was 0.74. For classification into subgroups, kappa values ranged from 0.48 to 0.78. For 85% of the areas classified endoscopically as Group I (n = 146), no mucosal lesions or gastritis was described at histologic examination; for 83% of those in Group II (n = 198), intestinal metaplasia was found. Subgroups IIA and IIB were more often associated with complete intestinal metaplasia (62%), and IIC and IID with incomplete metaplasia (67%); in Group III (n = 118), dysplasia was diagnosed histopathologically in 33%. For the diagnosis of dysplasia, specificity was 81% (95% CI [77%, 85%]) and negative predictive value 99% (95% CI [99%, 100%]). CONCLUSIONS: Gastric endoscopic patterns with chromoendoscopy and magnification seem reproducible and valid for the diagnosis of lesions associated with gastric cancer. This procedure may improve the follow-up of individuals at high-risk of gastric cancer, at least for the exclusion of severe lesions.

Color↗
PubMed2003

Patterns of beta-catenin expression in gastric carcinoma: clinicopathological relevance and mutation analysis.

Studies on the expression of beta-catenin (beta-ct) in gastric carcinoma have provided conflicting results, and the role played by beta-ct mutations in gastric carcinogenesis remains unclear. In an attempt to clarify the aforementioned issues we undertook the retrospective study of 157 gastric carcinomas by using immunohistochemistry and molecular genetics. Reduced/absent membranous beta-ct expression was significantly associated with isolated-cell/diffuse histotype both in "pure" diffuse gastric carcinomas and in the isolated-cell/diffuse component of mixed carcinomas. Cytoplasmic and/or nuclear beta-ct expression was particularly prevalent in mixed carcinomas and was significantly associated with lymphatic vessel invasion and lymph node metastases. beta-ct mutations were not detected in any case. We conclude that the pattern of beta-ct expression is closely related to gastric carcinoma histotype. The activation of Wnt/beta-ct pathway is associated with mixed gastric carcinoma and with features of clinical aggressiveness; the mechanism(s) underlying this pathway in gastric carcinoma are not due to beta-ct mutations and remain to be elucidated.

Cell Nucleus↗
PubMed2002

A slow acetylator genotype associated with an increased risk of advanced cervical cancer.

PURPOSE: Human papillomavirus (HPV) is the major etiological agent associated with cervical cancer. However, other risk factors have been indicated, including carcinogen exposure, oral contraceptive usage, certain nutritional deficiencies, and genetic factors. N-acetyltransferase 2 (NAT2) has an important role in the metabolism of several carcinogens. NAT2 polymorphism modulates the activity of the enzyme, by activation, via O-acetylation, or through detoxification, via N-acetylation. This case-control study was designed to evaluate the association between NAT2 polymorphism and genetic susceptibility to cervical cancer. METHODS: Genomic DNA was obtained from 125 women with advanced cervical cancer and 170 healthy women. PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphisms) was used to analyse two common mutant alleles at NAT2 loci. RESULTS: The NAT2*6/NAT2*6 genotype, which corresponds to a slow acetylator genotype, was found to be associated with a 3.41-fold (95% CI: 1.35-8.94; P= 0.007) increase in the risk of cervical cancer. For the entire case groups the proportion of cervical cancer cases attributable (attributable proportion) to the NAT2*6/NAT2*6 genotype was 10.2%. CONCLUSIONS: The results reported in this study suggest that NAT2 polymorphism is a genetic susceptibility factor involved in the carcinogenesis of cervical cancer, and also that the analysis of the allelic profile of populations in different geographic locations may help to understand the incidence of cervical cancer worldwide.

Acetylation↗
PubMed2002

Linkage between polymorphisms in the prostate specific antigen ARE1 gene region, prostate cancer risk, and circulating tumor cells.

BACKGROUND: The prostate specific antigen (PSA) gene has a polymorphic androgen response element (ARE) sequence with two alleles, A and G. PSA A-allele carriers have higher serum PSA levels in healthy men (HM). METHODS: We analysed DNA samples from 278 (556 alleles) unrelated individuals, 127 HM and 151 prostate cancer (PC) patients, for PSA ARE1 genotypes. RESULTS: The analysis of the frequencies from the 556 alleles indicates a significant overrepresentation of A-allele in the PC group under the age of 67 compared with the HM group (63.3% vs. 48.8%; P = 0.009). We found that men carrying two A-alleles have increased risk for PC onset under the age of 67 (odds ratio [OR] = 2.92; 95% confidence interval [CI], 1.10-7.86; P = 0.013). Multivariate logistic regression analysis confirmed this association (OR = 1.82; 95% CI, 1.03-3.22; P = 0.037). Furthermore, the homozygosity for the A-allele was associated with higher serum PSA levels (P = 0.027) and with the presence of circulating tumor cells in the blood of PC patients (P = 0.018). CONCLUSION: Our results indicate that polymorphism in the PSA gene promoter may be an important biomarker for prostate cancer risk, especially for an earlier onset of PC.

Adult↗
PubMed2002

The role of vitamin D receptor gene polymorphisms in the susceptibility to prostate cancer of a southern European population.

Epidemiological data indicate a relationship between ultraviolet radiation, vitamin D, and prostate cancer risk. Antiproliferative effects of vitamin D require the expression of the nuclear vitamin D receptor (VDR). A three-fold increase in prostate cancer risk associated with the less active vitamin D receptor allele (the T allele from VDR TaqI polymorphism at codon 352) was reported. The role of VDR genotypes in the susceptibility to prostate cancer has not yet been studied in populations of southern Europe. In the present study, we determined VDR TaqI genotypes in Portuguese prostate cancer cases ( n = 163) and controls ( n = 211), a southern European population. When cases were compared with controls, we found an association of VDR T allele with prostate cancer risk (odds ratio [OR] = 1.87, 95% confidence interval [CI] 1.02-3.37; P = 0.035). This association was confirmed using logistic regression analysis (OR = 2.11, 95% CI 1.15-3.88; P = 0.015) and in particular associated to risk of prostate cancer onset in men over the age of 66 years (OR = 2.36, 95% CI 1.05-5.29; P = 0.036). Fifty percent of cases older than 66 years could be attributed to the influence of this risk factor. Our results indicate that the contribution of VDR genotypes to prostate cancer susceptibility might depend on the population studied and its geographic localization, and that VDR genotypes are important in the definition of the genetic risk profile of populations of southern Europe.

Aged↗
PubMed2002

Quantitative GSTP1 hypermethylation in bodily fluids of patients with prostate cancer.

OBJECTIVES: To further determine the value of real-time quantitative methylation-specific polymerase chain reaction (MSP) of GSTP1 as a molecular tool for the detection of prostate adenocarcinoma. Recent studies have shown a high frequency (more than 90%) of GSTP1 gene promotor methylation in prostate adenocarcinoma and a lower frequency in DNA from serum and urine. METHODS: Tissue samples from 69 patients with early-stage prostate adenocarcinoma and 31 patients with benign prostatic hyperplasia were collected. Matched urine and plasma specimens were obtained preoperatively. After sodium-bisulfite treatment, extracted DNA was analyzed for GSTP1 promoter hypermethylation both by conventional and real-time quantitative MSP. RESULTS: In tissue samples, GSTP1 hypermethylation was detected in 63 (91.3%) of the 69 patients with cancer and in 9 (29%) of the 31 patients with benign prostatic hyperplasia. Conventional MSP detected GSTP1 hypermethylation in a larger number of urine and plasma samples than did real-time quantitative MSP (53.6% versus 31.9%, overall). In all positive bodily fluids, the paired tumor was also confirmed to be methylated. GSTP1 hypermethylation was detected by both MSP methods in only one urine sample (3.2%) from a patient with benign prostatic hyperplasia. CONCLUSIONS: Although not quantitative, conventional MSP is currently more sensitive than real-time quantitative MSP in the detection of GSTP1 hypermethylation in bodily fluids from patients with prostate cancer with clinically localized disease. The value of quantitative determinations in monitoring and risk assessment remains to be further explored.

Adenocarcinoma↗
PubMed2002

I105V polymorphism and promoter methylation of the GSTP1 gene in prostate adenocarcinoma.

The GSTP1 gene encodes for an enzyme, glutathione S-transferase pi (GSTpi),involved in detoxification of carcinogens. An aminoacid substitution (I105V) in GSTP1 produces a variant enzyme with lower activity and less capability of effective detoxification. This variant GSTP*B allele has been associated with a propensity to develop several neoplasms. Because GSTP1 promoter hypermethylation and inactivation of GSTpi expression is a frequent alteration in prostate carcinoma, we hypothesized that this somatic epigenetic modification could obviate any reduced enzyme activity caused by the germ-line polymorphism. We tested for the GSTP1 genotype in a population of prostate cancer patients, and in a control group composed of patients with benign prostatic hyperplasia (BPH) and healthy blood donors. Tissue samples from the 105 prostate cancer cases (105 adenocarcinomas and 34 prostatic intraepithelial neoplasia lesions), and from 43 BPH patients were tested for GSTP1 hypermethylation by methylation-specific PCR. GSTpi protein expression was assessed by immunohistochemistry. No significant effect on prostate cancer risk was detectable for GSTP1 genotype compared with the control population (odds ratio, 1.02; 95% confidence interval, 0.59-1.75). Moreover, no association was found between this genotype and tumor or BPH methylation status. Patients with unmethylated carcinomas did not disclose significant differences in genotypic distribution compared with the control population. In adenocarcinoma, a strong association (P < 0.00001) between GSTP1 promoter hypermethylation and loss of GSTpi expression was observed; however, this trend was not retained in prostatic intraepithelial neoplasia or BPH lesions. Although the GSTP1 polymorphism is not associated with altered susceptibility to prostate cancer, somatic promoter hypermethylation is an effective, but not the only, cause of decreased GSTpi function.

Adenocarcinoma↗
PubMed2002

Outcome in prostate cancer: association with endothelial nitric oxide synthase Glu-Asp298 polymorphism at exon 7.

PURPOSE: The endothelial cell-specific form of nitric oxide synthases (ecNOS) was mapped at 7q35-q36 and plays an important role in vascular development and tumor growth in human prostate cancer. Bone metastasis, clinical T-stage, tumor grade, and serum prostate-specific antigen (PSA) have been shown to have prognostic importance in the outcome of prostate cancer. The purpose of this study was to evaluate ecNOS polymorphism as a genetic indicator of the outcome of the disease. EXPERIMENTAL DESIGN: In this study, we characterized the Glu-Asp298 ecNOS polymorphism in a series of 161 prostate cancer cases. Logistic regression models were used to assess the contribution of these genotypes to prostate cancer progression. RESULTS: For Glu-Asp298 polymorphism, we found that GG genotype was associated to advanced disease [P = 0.020; odds ratio (OR), 2.12; 95% confidence interval (CI), 1.12-4.03] and bone metastasis (P = 0.038; OR, 2.23; 95% CI, 1.03-4.84). Furthermore, after logistic regression analysis with step-wise routine to identify predictive parameters of metastasis, which included age at diagnosis, advanced stage, GG genotype, high grade, and high serum PSA, we observed that Glu-Asp298-GG genotype (P = 0.004; OR, 7.4; 95% CI, 1.87-29.26), high grade tumor (P = 0.009; OR, 6.15; 95% CI, 1.56-24.17), and high serum PSA (P < 0.001; OR, 245.12; 95% CI, 19.93-3013.90) were significantly associated with bone metastasis. CONCLUSIONS: This study demonstrates a strong association between Glu-Asp298-GG genotype as a nitric oxide-related genetic factor and advanced disease and bone metastasization. The establishment of a genetic profile for each patient may be useful in the prediction of the outcome of prostate cancer patients.

Aged↗
PubMedDate not supplied

Polymorphisms of arylamine N-acetyltransferase (NAT1 and NAT2) and larynx cancer susceptibility.

Our aim was to examine the role of NAT1 and NAT2 polymorphisms in human larynx cancer susceptibility. Genotype tests for NAT1 alleles *4, *10 and *11, and NAT2 alleles *4, *5, *6A and *7A, using PCR-RFLP analysis, were performed in 172 healthy Portuguese individuals and 88 patients with squamous cell carcinoma of the larynx. NAT1 and NAT2 genotype frequencies were correlated between patients and control groups, using the chi-square test. Odds ratios and 95% confidence intervals were calculated from 2 x 2 tables with the Fisher's exact model. The statistical analysis of NAT1 and NAT2 genotype frequencies revealed a significant difference of NAT1*10/*11 (p = 0.038) and NAT2*5/*7 (p = 0.003) genotype distribution between cases and controls. We also observed differences concerning tumor location, since NAT1*10/*11 genotype frequency was significantly different when comparing normal control individuals with the glottic subgroup of patients. The present data suggest that NAT1 and NAT2 polymorphisms may be correlated with an increased risk of larynx cancer.

Acetyltransferases↗