Abstract: The Y chromosome has been suggested to play a role in prostate cancer (PCa) because the loss of this chromosome is the most common aberration in PCa. Study of short tandem repeats (STRs) could provide a means to rapidly scan genomes at known or unknown predisposing loci for some diseases. DNA samples from 281 patients with PCa at the Portuguese Institute of Oncology, Porto, Portugal, and a population control of 175 healthy controls were analyzed for region Yp11.2 using AmpFlSTR Y-Filer kit (Applied Biosystems). The results demonstrated that microvariant alleles of DYS458 are overrepresented (p = 0.026). We found that allele 12 of DYS393 and allele 19 of DYS458 could have a protective effect (p = 0.0051; odds ratio [OR] = 0.48; 95% confidence interval [95% CI] 0.27-0.38; and p = 0.0272; OR = 0.47; 95% CI 0.22-0.98). On the other hand, patients carrying allele 13 of DYS393 presented an increased risk to PCa (p = 0.015; OR = 1.97; 95% CI 1.26-3.07). These results are in concordance with the involvement of Y chromosome in PCa development. STR allele studies may add further information from the definition of a genetic profile of PCa resistance or susceptibility. As TSPY is located at region Yp11.2, this gene could play an essential role in PCa development.
Abstract: OBJECTIVE: COX-2, the inducible isoenzyme, was found to be overexpressed in approximately 85% of colorectal adenocarcinomas, contributing to key steps in tumor development. COX-2 polymorphisms that might modify the levels of protein expression would be anticipated to have a substantial influence on disease phenotype. Therefore, we sought to understand the role of three COX-2 polymorphisms (-1195A>G, -765G>C, and 8473T>C) in colorectal cancer (CRC) onset. MATERIAL AND METHODS: We conducted a hospital-based case-control study involving 117 consecutively enrolled CRC patients and 256 healthy individuals without any clinical evidence of cancer. The COX-2 polymorphisms' genotypes were characterized by PCR-restriction fragment length polymorphism or real-time PCR techniques. RESULTS: The -1195A>G polymorphism was associated with a 1.73-fold increased predisposition to CRC onset. In a stratified analysis, men and ever-smokers carrying -1195G allele (AG+GG) had an increased risk for CRC development (odds ratio: 2.58; 95% confidence intraval: 1.29-5.15 and odds ratio: 10.3; 95% confidence intraval: 3.37-31.2, respectively). More interestingly, men ever-smokers carrying -1195G allele appeared to have a nine-fold increased risk for CRC onset (95% CI: 2.94-27.6). No difference in the genotype's distribution was noticed between cases and controls for the remaining two polymorphisms. CONCLUSION: The -1195A>G COX-2 polymorphism seems to modulate the genetic susceptibility for CRC onset, especially in men ever-smokers. This genetically based higher-risk group definition may help shift the balance between risk and benefits for the use of COX-2 inhibitors in chemoprevention that is currently hampered by the adverse gastrointestinal and cardiovascular side-effects.
Abstract: Caveolin-1 (Cav-1) is a major structural protein of caveolae, plasma membrane invaginations related to several cellular processes including regulation of signal transduction. In recent years there has been some controversy regarding the distribution of Cav-1 in normal and neoplastic mammary cell types, which may be attributed to different scoring systems adopted in different studies. The present study compares Cav-1 immunoexpression in normal (n=17) and neoplastic (n=79) canine mammary tissues assessed by two different scoring methods (previously reported by others with conflicting results) and associates Cav-1 expression with metastasis and overall survival (OS). Results obtained with both scoring methods were similar, revealing absence of immunoreactivity in normal luminal epithelium and in benign neoplasms and clearly associating Cav-1 expression with malignant transformation. The data suggest that Cav-1 expression is associated with highly malignant subtypes of mammary tumours (i.e. basal-like carcinoma), invasion and metastasis, thus supporting the hypothesis that it may play a major role in the epithelial-mesenchymal transition process. Furthermore, one of the scoring systems employed associated Cav-1 expression with unfavourable prognosis in canine mammary carcinomas, showing a strong correlation between Cav-1-positive carcinomas and shorter OS.
Abstract: PURPOSE: Lung cancer continues to be the most frequent cancer with approximately one million people worldwide dying of this disease each year. Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of all lung cancers. The RAD51 protein is the key protein for homologous recombination, an evolutionarily conserved mechanism for DNA damage repair and the generation of genetic diversity. We conducted this study in order to investigate the effect of the RAD51 G135C polymorphism in treatment response to combined platinum taxanes/gemcitabine first line chemotherapy in NSCLC patients. METHODS: We analysed RAD51 G135C polymorphism in 243 NSCLC patients using PCR-RFLP methodology. RESULTS: There were no statistically significant differences between the groups of NSCLC patients with the different genotypes regarding tumour stage (p = 0.232). Our results indicate that the mean survival rates were statistically different according to the patient's genotypes. The group of patients carrying the C allele presented a higher mean survival rate than the other patients (56.0 months vs. 41.7 months; p = 0.024). Moreover, regarding smoking history, our results demonstrate that overall survival time differed significantly according to the patient's genotypes in smoker and ex-smoker individuals (p = 0.034). No statistically significant differences were found in the genotype frequencies and overall survival rate among non-smoker NSCLC patients (p = 0.413). CONCLUSIONS: This is the first study evaluating the effect of the RAD51 G135C polymorphism in NSCLC patient survival. Our results suggest that RAD51 genotypes could be useful molecular markers for predicting the clinical outcome of NSCLC patients.
Abstract: Solid tumors usually occur and progress in a hypoxic environment, suggesting that tumor cells are resistant to apoptosis and are associated to an increased angiogenesis, which makes them more aggressive, with invasive capacity and resistant to treatment. The genetic and biological mechanisms underlying this phenomenon are still unclear, but many studies suggest a role of HIF in this process. Under hypoxic conditions, the alpha subunit is not destroyed, and will activate transcription of a set of genes contributing to tumor aggressiveness. Its expression is associated to an increased metastatic potential that has been shown in both animal studies and human tumors. Tumor hypoxia has emerged as a key factor in tumor progression and is associated to a poor prognosis, particularly in kidney and prostate tumors. The purpose of this study was to review the significance of hypoxia in carcinogenesis and tumor progression by reviewing the current knowledge on the subject and the mechanisms of action and activation of HIF-1a Tumor hypoxia has emerged as a key factor in tumor progression and is associated to a poor prognosis, particularly in kidney and prostate tumors. The purpose of this study was to review the significance of hypoxia in carcinogenesis and tumor progression by reviewing the current knowledge on the subject and the mechanisms of action and activation of HIF-1a.
Abstract: Proliferative mechanisms involving the epidermal growth factor (EGF) and transforming growth factor beta (TGF-beta(1)) ligands are potential alternative pathways for prostate cancer (PC) progression to androgen independence (AI). Thus, the combined effect of EGF and TGFB1 functional polymorphisms might modulate tumor microenvironment and consequently its development. We studied EGF+61G>A and TGFB1+869T>C functional polymorphisms in 234 patients with PC and 243 healthy individuals. Intermediate- and high-proliferation genetic profile carriers have increased risk for PC (odds ratio (OR)=3.76, P=0.007 and OR=3.98, P=0.004, respectively), when compared with low proliferation individuals. Multivariate analysis showed a significantly lower time to AI in the high proliferation group, compared with the low/intermediate proliferation genetic profile carriers (HR=2.67, P=0.039), after adjustment for age, metastasis and stage. Results suggest that combined analysis of target genetic polymorphisms may contribute to the definition of cancer susceptibility and pharmacogenomic profiles. Combined blockage of key molecules in proliferation signaling pathways could be one of the most promising strategies for androgen-independent prostate cancer.
Abstract: OBJECTIVE: Cyclooxygenases (COX) are important enzymes not only in the maintenance of mucosal integrity but also in pathological processes, namely in inflammation and tumor development in the gastrointestinal tract. Our goal was to understand whether there is a clear role for COX polymorphisms in gastric and colorectal carcinogenesis. METHODS: A systematic review was conducted on observational studies assessing the involvement of COX polymorphisms at the onset of gastric or colorectal lesions, retrieved through a MEDLINE database search by May 2008. The dominant genetic model was assumed for each polymorphism and a random-effect model was used for pooling results. RESULTS: Twenty-two studies were retrieved reporting a total of 26 COX polymorphisms (nine in COX1 and 17 in COX2 genes). Carriers of -1329A, -899C alleles, and *429TT genotype revealed increased risk for gastric cancer [odds ratio (OR)=1.83; 95% confidence interval (CI): 1.07-3.10, OR=2.02; 95% CI: 1.00-4.10 and OR=1.34; 95% CI: 1.06-1.71, respectively). For colorectal lesions, the -899G>C and -1329G>A polymorphisms also showed an increased risk for cancer (OR=1.35; 95% CI: 1.01-1.81 and OR=1.36; 95% CI: 1.11-1.66, respectively). Furthermore, C allele carriers of V102V single nucleotide polymorphisms presented a decreased risk for colorectal adenoma onset (OR=0.77; 95% CI: 0.58-1.03). CONCLUSION: Although further studies, namely cohorts and/or adequately matched case-control studies, are required to unravel the impact of most COX polymorphisms, clearly there are evidences that support the involvement of -899G>C and -1329G>A COX2 polymorphisms in either gastric or colorectal carcinogenesis. These markers could be used to optimize management strategies (follow-up and/or chemoprevention).
Abstract: Growth factors play an essential role in regulating cellular proliferation, and lack of control is characteristic of malignant development. The epidermal growth factor (EGF) gene codifies a growth factor that binds to the EGF receptor (EGFR), which is involved in activating pathways that promote cellular proliferation, survival, migration and differentiation. The purpose of this study was to appraise the association between EGF gene A61G polymorphism with ovarian cancer susceptibility. A total of 564 DNA samples were analysed from 175 women with ovarian cancer and 389 women without cancer, through PCR-RFLP. We found a decreased risk for developing ovarian cancer in GG carriers compared to AA carriers (OR = 0.46, CI = 0.25-0.83, P = 0.010). The seemingly protective role in GG carriers was observed in women under 53 years of age (OR = 0.38, CI = 0.16-0.86, P = 0.011) and in patients diagnosed with advanced stage disease (OR = 0.38, CI = 0.18-0.81, P = 0.012). Allelic comparison evidenced similar results, with decreased risk for G allele. We further observed a linear trend for G allele in cancer risk. Moreover, we analysed the influence of genotypes in the time to onset of the disease and observed that GG carriers had ovarian cancer later than AA carriers (P = 0.035). We hypothesize that this polymorphism confers protection for ovarian cancer development.
Abstract: COX-2 expression was examined immunohistochemically in samples of normal canine mammary tissue (n=22) and benign (n=36) and malignant (n=45) mammary tumours including metastases (n=12). COX-2 was constitutively expressed in normal mammary tissue with membranous apical labelling of glandular epithelium, suggesting a role for this molecule in normal mammary physiology. By contrast, in neoplastic lesions and in adjacent non-neoplastic mammary tissue COX-2 was expressed in the cytoplasm of epithelial cells, suggesting that internalization of the molecule is associated with oncogenesis. Marked expression of COX-2 was observed in 8.3% of benign neoplasms and in 42.2% of malignant neoplasms, mainly in poorly differentiated areas. The majority of metastatic lesions (58.3%) exhibited strong COX-2 labelling and in almost all cases (83.3%) the labelling intensity was similar or stronger to that of the primary neoplasm. This finding is consistent with the hypothesis that COX-2 metabolites are important promoters of angiogenesis and invasiveness and therefore contribute to metastatic spread.
Abstract: Catechol-O-methyltransferase (COMT) is an important enzyme involved in inactivation of catechol estrogens, which are metabolites with carcinogenic properties. Some investigations in human breast cancer associate a genetic polymorphism in the COMT gene (COMT val158met) with an increased risk and poor clinical progression of the disease. In dogs, there are 2 recognized single nucleotide polymorphisms in the COMT gene (COMTG216A and COMTG482A); however, their influence on the outcome of mammary neoplasms has never been investigated. The purpose of this study is to investigate the influence of COMT in the clinical progression of canine mammary tumors, namely in recurrence, metastasis and survival by testing 2 SNPs (G216A and G482A), and 2 genotypes of the COMT gene. A case series was conducted analyzing genomic DNA samples by polymerase chain reaction-restriction fragment length polymorphism from 80 bitches with mammary tumors. Animals were submitted to an active follow-up study for a period of 24 months after surgery. We observed that bitches carrying both genetic variations simultaneously are more likely to develop recurrence of mammary lesions. Our results demonstrate a possible role for COMT genotypes in the outcome of mammary neoplasms in the dog. Identifying a genetic factor predictive of recurrence may be useful in selecting the most effective surgical approach for canine mammary neoplasms.
Abstract: Growth factors are important mediators of proliferation. Deregulation in growth factor mechanisms as well as in its receptors will contribute to cancer development. One of the most important is the epidermal growth factor (EGF), which is encoded by EGF gene. A functional polymorphism at position 61 (A/G) is associated with increased expression of EGF. Thus, we proposed to assess genotype frequencies in a case-control study and appraise their association to breast cancer risk. Using the polymerase chain reaction technique combined with restriction enzyme fragment length polymorphism (PCR-RFLP) we analyzed DNA from 883 women (500 controls and 383 breast cancer patients). Our results suggested that carriers of G homozygous genotype had a lower risk for developing breast cancer (odds ratio = 0.68; 95% confidence intervals, 0.46-1.01). Further, we showed that the waiting time for onset of breast cancer in G homozygous patients for EGF genotypes (55 years) was significantly lower in comparison to A-allele carriers (59 years) (log-rank test: p = 0.038). EGF is produced in mammary tissue and acts in the mammalian development. A lower risk for breast cancer in GG carriers might be explained through EGF receptor internalization promoted by EGF.
Abstract: We aimed to study the role of an insertion/deletion polymorphism in the Pepsinogen C (PGC) gene in the clinical outcome of 172 breast cancer patients. The six polymorphic alleles were amplified using PCR. Our results indicate that patients carrying the allele 6 present a higher 5-year survival mean (83.4% of 6 allele carriers were alive at 5 years vs. only 68.6% of noncarriers, p=0.001), suggesting a role for this polymorphism in the outcome of breast cancer patients. We hypothesize that PGC polymorphism can be a predictive biomarker in breast cancer, contributing to an individual profile of great interest in clinical oncology.
Abstract: Rituximab is a chimeric monoclonal antibody that specifically targets the CD20 surface marker expressed in neoplastic B-lymphoid cells. Combined with chemotherapy or alone, in maintenance/consolidation, it is used for the treatment of non-Hodgkin lymphoma (NHL). The role of a polymorphism in a specific Fc gamma receptor gene, FcgammaRIIa, in the clinical outcome of patients with NHL was investigated in this study. We characterized DNA samples from 64 non-Hodgkin lymphoma patients treated with rituximab using a polymerase chain reaction-restriction fragment length polymorphism method. The FcgammaRIIa HH genotype was significantly correlated with complete response to rituximab compared to the R allele (P=0.028). In terms of overall or event-free survival, no difference was found according to FcgammaRIIa alleles. We hypothesize that the HH genotype increases the affinity of the FcgammaRIIa receptor, not only for naturally occurring IgG2, but also to ameliorate connection with chimeric IgG1 rituximab, contributing to a genetic individual profile of great interest in clinical onco-hematology.
Abstract: PURPOSE: Most prostate cancer patients develop resistance to androgen deprivation treatment, resulting in hormone resistance. Epidermal growth factor (EGF) activates several pro-oncogenic intracellular pathways inducing proliferation, differentiation, and tumorigenesis in epithelial cells. The EGF-EGF receptor pathway seems to be especially relevant in hormone-resistant prostate cancer stage. A single nucleotide polymorphism G>A in +61 locus of EGF gene has been described, in which A homozygous carriers express significantly less EGF protein compared with G allele carriers. Our purpose was to investigate the potential prognostic and predictive role of EGF functional genetic variant +61 G>A in prostate cancer patients submitted to androgen blockade therapy (ABT). EXPERIMENTAL DESIGN: We conducted a case-control study in prostate cancer patients treated with ABT (n = 123) and in healthy controls without evidence of cancer (n = 152). Cumulatively, a follow-up study (median follow-up, 37 months) was undertaken to evaluate response to ABT therapy in prostate cancer patients. EGF +61 G>A genotypes were detected by PCR-RFLP. RESULTS: We found increased risk in G carriers, after age-adjusted regression analysis, for being diagnosed with Gleason > or =7 and with metastatic disease compared with control group (CG; age-adjusted odds ratio, 3.37, P = 0.004 and age-adjusted odds ratio, 2.61, P = 0.043, respectively). Kaplan-Meier survival analysis and log-rank test showed an influence of EGF +61 G>A polymorphism in time to relapse during ABT (P = 0.018). CONCLUSIONS: EGF functional polymorphism may contribute to earlier relapse in ABT patients, supporting the involvement of EGF as an alternative pathway in hormone-resistant prostatic tumors. Furthermore, our results lend support to EGF-EGF receptor pathway as an additional therapeutic target during hormonal treatment.
Abstract: Nasopharynx is a particular anatomic structure, located between the respiratory and digestive systems, and it is the geographic centre of all otorinolaringologic pathologies. Numerous filogenic, ontogenic and embryogenic factors contribute to the anatomic and physiologic structure of nasopharynx. These factors may directly contribute to the development of several pathologies, as the embryogenic pathology, or even in an indirect way, through the interaction with the environment, as the inflammatory and neoplastic pathologies, of which the nasopharyngeal carcinoma acquires great significance. The objective of this study was to endorse the importance of a multidisciplinary approach in the study of nasopharynx, contributing to a wider knowledge about the different kinds of diseases associated with this anatomic structure.
Abstract: Catechol-O-methyltransferase (COMT) is an important enzyme participating in inactivation of carcinogenic oestrogen metabolites. In humans there is a single nucleotide polymorphism in COMT gene (COMT val158met) that has been associated with an increased risk for developing breast cancer. In dogs, there is a single nucleotide polymorphism in COMT gene (G482A), but its relation with mammary carcinogenesis has never been investigated. The aim of this study was to focus on the evaluation of such polymorphism as a risk factor for the development of mammary tumors in bitches and on the analysis of its relationship with some clinicopathologic features (dog's age and weight, number and histologic type of the lesions, lymph node metastasis) of canine mammary neoplasms. A case-control study was conducted analyzing 90 bitches with mammary tumors and 84 bitches without evidence of neoplastic disease. The COMT G482A polymorphism was analyzed by PCR-RFLP. We found a protective effect of the polymorphism in age of onset of mammary tumors, although we could not establish a significant association between COMT genotype and other clinicopathologic parameters nor with mammary tumor risk overall. Animals carrying the variant allele have a threefold likelihood of developing mammary tumors after 9 years of age in comparison with noncarriers. The Kaplan-Meier method revealed significant differences in the waiting time for onset of malignant disease for A allele carrier (12.46 years) and noncarrier (11.13 years) animals. This investigation constitutes the first case-control study designed to assess the relationship between polymorphic genes and mammary tumor risk in dogs. Our results point to the combined effect of COMT genotype with other genetic and/or environmental risk factors as important key factors for mammary tumor etiopathogenesis.
Abstract: Cyclin D1 (CCND1) is a key regulatory protein at the G1/S checkpoint of the cell cycle. The purpose of our study was to assess the role of CCND1 genotypes influencing the age of onset of oncogenic virus-associated neoplasia. We conducted a hospital-based case-control study of 581 individuals, including 247 controls and 334 cases (108 nasopharyngeal and 226 cervical cancer cases). The polymorphism analysis was performed in blood samples by PCR-RFLP methodology. Age-adjusted logistic regression analysis indicates that individuals carrying two G-alleles have an increased genetic susceptibility for the development of oncogenic virus-associated cancers (aOR=2.02, 95% CI 1.30-3.14, P=0.002). Moreover, our results indicate that the waiting time for onset of oncogenic virus-associated neoplasia in patients homozygous (GG) for CCND1 genotypes (52 years) was 12 years earlier in comparison with patients carrying AG or AA genotypes (60 years) (log-rank test: P=0.0003). Our results may be important in contributing to a more extensive knowledge of the mechanisms involved in oncogenic virus-associated carcinogenesis, as CCND1 may be an important target for the development of new strategies for cancer treatment and prevention.
Abstract: The role of FAS polymorphisms in prostate cancer has not been studied. Using the PCR-based restriction fragment-length polymorphism methodology, we evaluated FAS gene locus -670 genotypes in DNA from 904 men: 657 prostate cancer patients and 247 healthy controls. We found that carriers of AG or GG genotypes have a statistically significant protection (odds ratio (OR)=0.30; confidence interval (CI): 0.20-0.44 and OR=0.22; CI: 0.12-0.74, respectively) for disease with extra-capsular invasion. Taken together, a 72% protection was found for G allele carriers (OR=0.28; CI: 0.19-0.41). Fas exist as membrane-bound and soluble forms and with opposite roles. They derive from the same gene by alternative splicing. Membrane Fas receptors trigger apoptosis whereas, on the other hand, soluble Fas (sFas) bind to Fas ligand antagonizing Fas-Fas ligand apoptotic pathway. Our results suggest that G allele may reduce sFas levels preventing the apoptotic inhibition caused by the soluble form.
Abstract: The interaction between the E6 protein of the high-risk human papillomaviruses (HPVs) with p53 seems to be crucial in cervical carcinogenesis. The presence of Arg/Arg genotype at codon 72 of TP53 gene was characterized as a risk factor in development of cervical cancer. However, the role of this polymorphism remains controversial and some authors suggested that the origin of DNA (blood or exfoliated cervical cells) might influence these results. This study analyzed the effect of the p53 codon 72 polymorphism (R72P) in exfoliated cervical cells of women from the northern region of Portugal using two methodologies: allele-specific polymerase chain reaction and real-time polymerase chain reaction. We studied 700 cervical exfoliated cells which showed: 334 cases from women without cervical cancer or cervical lesion (N), 114 low-grade squamous intraepithelial lesions (LSIL), 107 high-grade squamous intraepithelial lesions (HSIL), 20 invasive cervical cancers (ICC) and 125 atypical squamous cells of unknown significance (ASCUS). No statistically significant differences between cases and controls were found, regarding the influence of the R72P polymorphism with cytological classification, high risk-HPV infection and HPV16 presence (P = 0.336, P = 0.945, and P = 0.964, respectively). Also, the influence of this polymorphism in the median age of onset for LSIL, HSIL, and ICC was not statistically significant (P = 0.674, P = 0.810, and P = 0.928, respectively). Therefore, the hypothesis that women with Arg/Arg genotype have an increased risk of developing cervical cancer failed to be proven in this study. Moreover, our study reveals that results using exfoliated cervical cells are reliable as compared with studies on blood.
Abstract: BACKGROUND: TP53 is one of major tumour suppressor genes being essential in preservation of genome integrity. Two very common polymorphisms have been demonstrated to contribute to cancer susceptibility and tumour behaviour. The purpose of this study was to evaluate the role of Arg72Pro and PIN3 Ins16bp polymorphisms in TP53 gene as genetic susceptibility and predictive markers to breast cancer. METHODS: We analysed DNA samples from 264 breast cancer patients and 440 controls, for TP53 Arg72Pro and PIN3 Ins16bp polymorphisms using PCR-RFLP. RESULTS: We observed that women with A2A2 genotype have increased risk for developing breast cancer, either in women with or without familial history (FH) of the disease (OR = 4.40, 95% CI 1.60-12.0; p = 0.004; OR = 3.88, 95% CI 1.18-12.8; p = 0.026, respectively). In haplotype analysis, statistically significant differences were found between TP53 Arg-A2 haplotype frequencies and familial breast cancer cases and the respective control group (OR = 2.10, 95% CI 1.08-4.06; p = 0.028). Furthermore, both TP53 polymorphisms are associated with higher incidence of lymph node metastases. CONCLUSION: Our findings suggest TP53 PIN3 Ins16bp polymorphism as a real risk modifier in breast cancer disease, either in sporadic and familial breast cancer. Furthermore, both TP53 polymorphisms are associated with higher incidence of lymph node metastases.
Abstract: AIM: To determine whether the amounts of circulating DNA could discriminate between breast cancer patients and healthy individuals by using real-time PCR quantification methodology. METHODS: Our standard protocol for quantification of cell-free plasma DNA involved 175 consecutive patients with breast cancer and 80 healthy controls. RESULTS: We found increased levels of circulating DNA in breast cancer patients compared to control individuals (105.2 vs. 77.06 ng/mL, p < 0.001). We also found statistically significant differences in circulating DNA amounts in patients before and after breast surgery (105.2 vs. 59.0 ng/mL, p = 0.001). Increased plasma cell-free DNA concentration was a strong risk factor for breast cancer, conferring an increased risk for the presence of this disease (OR, 12.32; 95% CI, 2.09-52.28; p < 0.001). CONCLUSIONS: Quantification of circulating DNA by real-time PCR may be a good and simple tool for detection of breast cancer with a potential to clinical applicability together with other current methods used for monitoring the disease.
Abstract: AIM: To examine the possible role of the Epstein-Barr Virus (EBV) in the development of gastric adenocarcinoma (GC). It is unclear whether EBV is involved in GC development or is a consequence of gastric inflammation secondary to immunosuppressive treatments. METHODS: A systematic review was carried out of all published observational studies on the temporal association between EBV and GC, with a view to determine a causal relationship. RESULTS: The present study showed that the worldwide crude prevalence of EBV in gastric adenocarcinoma was 8.29%. The prevalence varied from 7.08% for intestinal type and 9.82% for diffuse type of GC. It was observed that Western and Central Asian countries had a significantly higher frequency of EBV positive cases compared to South-Eastern countries. America had the highest EBV-GC prevalence whereas Europe had the lowest. CONCLUSION: The present review has demonstrated a high prevalence of EBV in gastric adenocarcinoma. However, studies designed to assess a temporal relationship and histological association using sensitive techniques should be carried out to establish the role of EBV in GC carcinogenesis.
Abstract: Human papillomavirus (HPV) is the necessary cause for cervical cancer development, and the interaction of HPV-E6 with p53 is known as the most important event in HPV-associated carcinogenesis. In vitro studies have suggested that HPV-E6 interacts more efficiently with the arginine (Arg) p53 variant at position 72 as it appears to be more susceptible to degradation through the ubiquitin proteasome pathway. However, few reports have corroborated this data, and the role of the p53 codon 72 polymorphism in the development of cervical cancer requires further elucidation. We performed a meta-analysis review of all studies published within European populations to summarize the overall risk of this polymorphism considering the influence of the geographical/ethnic location as an important factor in defining a genetic profile and the susceptibility for cervical cancer development. Our analysis revealed that the p53 Arg/Arg genotype does not seem to represent a risk marker for the development of cervical lesions in the majority of the European countries analysed. However, in countries with low incidence rates of cervical cancer, this polymorphism might represent a significant genetic marker.
Abstract: Worldwide, approximately 1.3 billion individuals are current smokers, and smoking is the second major cause of death. Currently, lung cancer is the most common type of cancer in Europe, and the third in the U.S. Until now, cytotoxic chemotherapy has had a limited impact on survival in metastatic non-small cell lung cancer (NSCLC). The central role of epidermal growth factor (EGF) and its receptor (EGFR) in lung carcinogenesis is well recognized. Genetic polymorphisms are variants in individual genomes that may be responsible for different functional molecular roles and contribute to variability in drug pharmacokinetic and pharmacodynamic processes. Herein, we review the literature on EGF and EGFR functions and activities, particularly the current role of their functional polymorphisms as related to NSCLC.
Abstract: The purpose of this study was to evaluate the role of polymorphisms in DNA repair genes as genetic indicators of susceptibility to familial and sporadic breast cancer. We analysed DNA samples from 285 breast cancer patients and 442 control subjects, for XRCC1 Arg399Gln, XPD Lys751Gln, RAD51 G135C and XRCC3 Thr241Met polymorphisms using PCR-RFLP. We observed that women carriers of XRCC1 399Gln genotypes and without family history of breast cancer have a protective effect concerning this disease (OR = 0.54 95% CI 0.35-0.84; p = 0.006). Furthermore, we found that carriers of XRCC3 241Met genotypes without FH have an increased susceptibility of breast cancer (OR = 2.21 95% CI 1.42-3.44; p < 0.001). Additionally, we verified an increased risk of breast cancer in women with FH and carrying RAD51 135C genotypes (OR = 2.17 95% CI 1.19-3.98; p = 0.012). Our results suggest XRCC1 Arg399Gln and XRCC3 Thr241Met DNA repair polymorphisms as important biomarkers to sporadic breast cancer susceptibility, as well as, RAD51 G135C polymorphism as a real risk modifier in familial breast cancer cases.
Abstract: The purpose of this study was to evaluate the role of XPD genotypes as genetic indicator of susceptibility to ovarian cancer. We have used a case-control study. We analysed DNA samples from 141 ovarian cancer patients and 202 control subjects, for three XPD polymorphisms using PCR-RFLP. We observed that Asn312Asn XPD genotype carriers have increased susceptibility of ovarian cancer (OR=2.46 95% CI 1.20-5.06; P=0.015). Furthermore, we found that carriers of Gln751Gln XPD genotype have an increased susceptibility of ovarian cancer (OR=3.40 95% CI 1.61-7.15; P=0.001). Asn312Asn and Gln751Gln are particularly associated with an early-stage of disease. Our results suggest an important role for Asn312Asn and Gln751Gln XPD polymorphisms in the susceptibility to ovarian cancer.
Abstract: The human polyomaviruses--BKV and JCV--are members of Polyomaviridae family and after primary infections they persist as latent infection especially in the kidneys. BKV reactivation is mainly related to urinary tract diseases and JCV reactivation can induce the disease progressive multifocal leukoencephalopathy. The aim of our study was to characterize the excretion of polyomaviruses in urine samples of healthy individuals from a Portuguese population. We analyzed 498 DNA samples using PCR-RFLP, the sequence amplified consisted in 176 or 173 bp within the antigen T region. Our results indicate that 23.9% of the samples were positive for JCV, 1.8% positive for BKV and 74.3% of the individuals were negative for both viruses. We observed an increased prevalence of JCV shedding in male individuals in comparison to female (P = 0.026). Furthermore, the shedding of both polyomaviruses was influenced by the age of individuals with a significant increase in individuals with more than 56 years old (P = 0.005). Our results show that the shedding of polyomavirus in urine of healthy individuals is highly variable between genders, is influenced by age and differs from region to region. Further studies are needed to evaluate the prevalence of polyomaviruses in healthy individuals, in order to understand the biological behaviour of these viruses.
Abstract: Testosterone exposure has been implicated in prostate carcinogenesis, and genes that alter its metabolism, such as CYP3A4, have been associated with prostate cancer susceptibility. The aim of our study was to assess the relationship between the CYP3A4 *1B polymorphism and its possible role in the development of prostate cancer. DNA samples obtained from the peripheral blood cells of 414 individuals diagnosed with prostate cancer and 337 healthy male donors were used in this case-control study. The CYP3A4*1B polymorphism was analyzed by polymerase chain reaction-restriction fragment length polymorphism methodology. We found no statistically significant differences in the distribution of the CYP3A4*1B genotypes between cases and controls (P = 0.470; odds ratio = 1.191; 95% confidence interval=0.740-1.918), as well as after the stratification of our analysis, according to important clinicopathologic parameters of prostate cancer. Our results suggest that the CYP3A4*1B polymorphism is not associated with prostate cancer risk within the Portuguese population.
Abstract: This is a short review focusing on leptin immunoinflammatory mechanisms that ultimately may contribute to lung cancer development. We explored the complex and intricate interaction of leptin with immune cells to propose a pathway of inflammation-associated lung cancer development.
Abstract: OBJECTIVE: Characterization of the clinical evolution of nasopharyngeal cancer (NPC) patients in a Portuguese population during 31 years of follow-up. MATERIALS AND METHOD: Three hundred and twenty patients with epidermoid nasopharyngeal carcinoma were selected for this study. Histological subtypes were analyzed along with survival rates after different treatment schemes and according to AJCC and UICC staging classification systems. RESULTS: The most frequent histological subtype was undifferentiated nasopharyngeal carcinoma. The AJCC-2001 staging classification was considered the most suitable system for survival prediction. Better survival rates were found in patients treated with adjuvant chemotherapy (cisplatin and 5-fluorouracil) and these findings were similar to other published results. CONCLUSIONS: Although adjuvant chemotherapy may reduce the likelihood of distant metastasis, the latter is still the main cause of death in our study. The distant metastasis rate remains the crucial problem and bringing it down is an ever closer goal and a challenge for the future.
Abstract: Invasive squamous cell carcinomas of the cervix arise from earlier, reversible precursor lesions called low- and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively). The aim of our study was to analyse the influence of the CCR2-64I polymorphism in the development of SIL due to its preponderant role in the cervical carcinogenesis and in the progression of these lesions to invasive cervical carcinoma. We conducted a case-control study, analyzing 565 Caucasian women from the north of Portugal. The CCR2-64I polymorphism was analysed through polymerase chain reaction followed by restriction fragment length polymorphism. The frequency of GG, GA and AA genotypes was 76.5, 23.5 and 0.0% respectively, in HSIL patients, and 87.8, 11.1 and 1.1% respectively, in the control group. The G allele frequency was 88.2% in the HSIL group and 93.4% in the control group. Regarding the A allele frequency, it was 11.8% in the HSIL group and 6.6% in the control group. Overall, the frequency of A carrier genotypes was higher in HSIL patients than in the control group (p = 0.013; OR = 2.21; 95%CI: 1.17-4.15), suggesting that CCR2-64I polymorphism might contribute to the establishment of HSIL, through the disruption of the naturally fragile immune response directed towards human papillomavirus infection.
Abstract: BACKGROUND: Nasopharyngeal cancer (NPC) is multifactorial, and the genetic background may be a crucial etiologic factor. Cyclin D1 (CCND1) is a key regulator of the cell cycle, and its altered activity is associated with the development of cancer. METHODS: We analyzed the A870G CCND1 polymorphism by polymerase chain reaction/restriction fragment length polymorphism (PCR-RFLP) in 281 individuals, including 94 patients with NPC and 187 healthy individuals. RESULTS: Our results indicate that individuals carrying two G alleles have a 2.17-fold increase in the risk for the development of NPC (odds ratio [OR], 2.17; 95% confidence interval [CI], 1.19-3.98; p = .016). Age-adjusted logistic regression analysis confirmed this association (adjusted odds ratio [aOR], 2.14; 95% CI, 1.14-4.04; p = .018). Multivariate analysis demonstrates an independent association between GG CCND1 genotype (aOR, 2.06), male sex (aOR, 2.66), and age at diagnosis (aOR, 2.02) regarding the development of undifferentiated NPC. The proportion of NPC cases attributable to the GG CCND1 genotype was 14.76%. CONCLUSIONS: Our results may be important in the definition of a biologic predictive profile for the development of NPC within our population.
Abstract: Genetic predisposition has been suggested as a cofactor for cancer aetiology and a polymorphism in TP53 codon 72 has been associated as a susceptibility factor for several cancers. Nasopharyngeal carcinoma is a rare neoplasia in western civilizations and genetic predisposition might play an important role in its development. We evaluated the linkage of the polymorphic variants (Arg/Pro) on TP53 codon 72 with nasopharyngeal cancer development in a case-control study with 392 individuals from a northern Portuguese population, including 107 patients with nasopharyngeal carcinoma and 285 healthy controls. This study revealed a three-fold risk for carriers of Pro/Pro genotype either against carriers of Arg/Arg (OR=2.62; 95% CI=1.10-6.30; P=0.016) or total Arg carriers (OR=2.67; 95% CI=1.21-5.90; P=0.012). Moreover, step-wise logistic regression analysis identified Pro/Pro genotype (OR=3.1; 95% CI=1.3-7.3; P=0.009), age >49 at diagnosis (OR=2.5; 95% CI=1.6-4.0; P<0.001) and male gender (OR=2.7; 95% CI=1.6-4.4; P<0.001) as predictive factors for the development of nasopharyngeal carcinoma. These results confirm the data from Asiatic populations suggesting that Pro/Pro genotype represents a stable risk factor for nasopharyngeal carcinoma development in Portugal and that TP53 codon 72 polymorphism can contribute as a genetic susceptibility marker, providing additional information to improve the knowledge about nasopharyngeal carcinoma aetiology.
Abstract: AIM: To study the role of an insertion/deletion polymorphism in the pepsinogen C (PGC) gene, an effective marker for terminal differentiation of the stomach mucosa, in the susceptibility to the development of gastric lesions. METHODS: The study was performed with 99 samples of known gastric lesions and 127 samples without evidence of neoplastic disease. PCR was employed and the 6 polymorphic alleles were amplified: Allele 1 (510 bp), Allele 2 (480 bp), Allele 3/4 (450/460 bp), Allele 5 (400 bp) and Allele 6 (310 bp). RESULTS: Our results revealed that Allele 6 carriers seemed to have protection against the development of any gastric lesion (OR = 0.34; P<0.001), non-dysplastic lesions associated with gastric adenocarcinoma such as atrophy or intestinal metaplasia (OR = 0.28; P<0.001) or invasive GC (OR = 0.39; P = 0.004). CONCLUSION: Our study reveals that the Allele 6 carrier status has a protective role in the development of gastric lesions, probably due to its association with higher expression of PGC. Moreover, the frequency of Allele 6 carriers in the control group is far higher than that obtained in Asian populations, which might represent a genetic gap between Caucasian and Asian populations.
Abstract: AIM: To investigate the relationship between the -765G > C COX-2 polymorphism and the development of different gastric lesions: atrophy or intestinal metaplasia and gastric adenocarcinoma. METHODS: A cross-sectional study was performed involving 320 Portuguese individuals (210 without evidence of neoplastic disease, 73 patients with gastric adenocarcinomas and 37 with atrophy or intestinal metaplasia) using a PCR-RFLP method. RESULTS: -765C allele was overrepresented in the patients with gastric adenocarcinoma (51%) when compared either with the control group (38%) or patients with atrophy or intestinal metaplasia (27%). Callele was found to be very common in our population (0.22), and a multivariate logistic regression analysis revealed nearly 3-fold increased risk for the progression to gastric adenocarcinoma in patients with atrophy or intestinal metaplasia carrying the -765C allele (OR = 2.67, 95% CI = 1.03-6.93; P = 0.04). CONCLUSION: -765C carrier status should be considered as another susceptibility marker for gastric adenocarcinoma development in patients with atrophy or intestinal metaplasia.
Abstract: Obesity-associated prostate cancer (PCa) remains controversial, although most studies rely on body mass index evaluation, which is an indirect measure of fatness. Studies using body fat measurement and disease stratification according to PCa stage found stronger associations between obesity and PCa. Leptin is a pleiotrophic hormone mainly synthesized by adipocytes that acts in peripheral organs such as the prostate. This article reviews obesity-associated leptin's pathophysiological role in PCa progression. PCa development results from some known risk factors. Currently, there is enough evidence suggesting that leptin is an additional factor involved in advanced PCa occurrence, and obesity association with high-grade disease. Life-long exposure to genetic and/or environmental susceptibility factors that predispose to obesity and higher leptin levels may increase the risk for advanced PCa.
Abstract: Ovarian cancer (OC) is the most lethal gynaecologic cancer and its standard treatment consists of platinum-based chemotherapy after cytoreductive surgery. The p53 protein plays a critical role on different cellular processes in response to DNA damage and it is responsible for transcriptional induction of the P21 gene. We have analysed 114 blood samples in order to investigate the effect of the TP53 codon 72 and the P21 3'UTR polymorphisms in response to cisplatinum/paclitaxel chemotherapy for OC treatment. The genotypes of the TP53 codon 72 and P21 3'UTR polymorphism were identified using AS-PCR and PCR-RFLP, respectively. Our results indicate that the TP53 P allele is associated with a worse prognosis (P=0.011) while P21 polymorphism genotypes did not reveal any statistically significant result (P>0.05). Furthermore, simultaneous carriers of the TP53 AA genotype and the P21 CC genotype demonstrate a longer progression-free interval (P=0.020). This study suggests that the characterisation of a genetic profile can contribute to the definition of a better chemotherapy treatment.
Abstract: TP53 and its downstream effector gene P21 are two important genes in cell cycle regulation. Genetic alterations on p53 and attenuation of p21 expression result in progression through cell cycle G1 checkpoint, which can lead to cancer development. We analysed the frequency of TP53 codon 72 and 3'UTR P21 polymorphisms in 681 blood samples from 371 cervical cancer patients, 122 ovarian cancer patients and 188 healthy controls using AS-PCR and PCR-RFLP. Approximately twofold increased risk of ovarian cancer (OC) was observed for TP53 Pro carriers (P = 0.038), with a significantly higher risk for advanced OC (P = 0.018). Furthermore, among the P21 CC genotypes, TP53 P allele was also associated with a twofold increased risk of OC (P = 0.014) and to a threefold increased risk for advanced OC (P = 0.003) with an attributable proportion of 44.2%. These results were confirmed in an age-adjusted logistic regression analysis. No association was found between these polymorphisms and cervical cancer. Our results suggest that the TP53 codon 72 genotypes may be considered as a molecular marker, contributing to a genetic profile for ovarian cancer in women.
Abstract: The present study examines the frequency of the two main HFE mutations (C282Y and H63D) in a randomly selected population of 346 individuals including 201 DNA samples from women with cervical neoplasia (including high-grade squamous intraepithelial lesions and invasive squamous cell carcinoma) and a control population of 146 women from the same geographical area. We found a significantly lower risk of development of cervical neoplasia in H63D carriers (OR = 0.56; 95% CI 0.35-0.92; p = 0.01). Multivariate logistic regression analysis confirms this observation (OR = 0.55; 95% CI 0.35-0.88, p = 0.01). Regarding the C282Y mutation no association was found (OR = 1.32; 95% CI 0.53-3.33; p = 0.52). In addition, a significant difference between H63D carrier and non-carrier women on the time-to-onset of cervical lesions was observed (log-rank test: p = 0.0012). These results indicate that HFE could be considered a candidate modifier gene of viral-related neoplasia such as cervical carcinoma possibly by a dual role on iron metabolism and immunological system.
Abstract: INTRODUCTION: Besides human papillomavirus (HPV) infection, several cofactors are considered important for the development of cervical cancer (CC). Among these, tobacco smoke, other sexually transmitted diseases, inflammation and nutritional factors have been intensively described. CYP2E1 polymorphisms have been associated with the metabolization of several carcinogens, some of them considered risk factors for CC development, such as tobacco smoke. The aim of this study was to evaluate the role of CYP2E1 polymorphisms in the susceptibility to cervical cancer in a Portuguese population. PATIENTS AND METHODS: The genotypic analysis was performed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) methodology, using peripheral blood samples of 454 individuals: 122 presented invasive squamous cell carcinoma (ICC), 59 presented squamous intraepithelial lesions (SIL), and the control population was composed of 274 healthy individuals. RESULTS: Concerning the DraI polymorphism, we observed a decreased risk for the development of squamous cervical lesions in the presence of the C allele [odds ratio (OR)=0.600; 0.378<OR<0.952; p=0.029]. In the stratification of the analysis according to the mean age, we observed an increased risk for the development of SIL, for women older than 39 years of age, in the presence of the D allele (OR=0.087; 0.012<OR<0.651; p=0.003). Regarding the RsaI polymorphism, we did not find any significant differences. CONCLUSION: The decreased risk observed for the development of SIL and not ICC in the presence of the D allele may indicate that CYP2E1 interferes with the initial steps of the carcinogenic process, probably due to its involvement in the action of immunological mediators, expressed during cervical inflammation. These aspects may help to define new therapeutic strategies for chemoprevention.
Abstract: Leptin hormone and receptor have been associated to cancer development and were identified in lung tissue. In this study, a functional polymorphism in the 5' flanking region of the leptin gene (LEP -2548 G/A) was found to increase susceptibility for non-small cell lung cancer [odds ratio (OR), 1.97; 95% confidence interval (CI), 1.13-3.43]. Age-adjusted logistic regression analysis in men indicated an association of AA genotype with adenocarcinoma (OR, 4.29; CI, 1.64-11.72) and squamous cell carcinoma (OR, 3.19; CI, 1.26-8.13). Logistic regression analysis confirmed the AA genotype as an independent risk factor for lung cancer after adjustment for age and gender (OR, 2.57; CI, 1.34-4.92). The AA genotype was overrepresented only in patients with non-metastatic disease (OR, 1.86; CI, 1.13-3.04). Kaplan-Meier analysis demonstrated an earlier age of onset for lung cancer in AA carriers (P=0.023). Results suggest the existence of genetic susceptibility for lung cancer in carriers of this LEP functional polymorphism. Further studies are warranted to extend knowledge of leptin involvement in lung cancer.
Abstract: A different prevalence of human papillomavirus (HPV) types has been reported in distinct populations. Although Portugal has a relatively high incidence of cervical cancer within the European Union, no studies have been reported in the Portuguese population. Recently, a clinical trial using a vaccine targeted against HPV-16 demonstrated a high efficacy in preventing HPV-16 cervical lesions. The aim of the present study was the characterization of HPV genotype profile in squamous intraepithelial lesions (SIL) and invasive cervical cancer (ICC) from 608 patients using polymerase chain reaction (PCR) methodology. We frequently detected HPV-6/11 and HPV-16 in low-grade SIL (HPV-6/11, 18.9%; HPV-16, 44.2%). In high-grade SIL, HPV-16 was demonstrated in 74.2% of those lesions and in 80.0% of the cases with ICC. HPV-18 was found in 3.1%, 0.8% and in 15.0% of low, high SIL and ICC, respectively. The overall prevalence of multiple infections with high-risk HPV was 7.2%. Other types of HPV were detected in 7.0% of all cases. Our results demonstrate a high prevalence of HPV-16 in SIL and ICC in Portuguese women. Therefore, a prophylactic HPV-16/18 vaccine may be effective in the prevention of cervical cancer in a significant number of women from this southern European population.
Abstract: OBJECTIVE: Invasive cervical cancer (ICC) is one of the most common malignant diseases among women, representing almost 10% of all the cancers in the female population. The aim of this study was to explore the association of the CCR2-64I polymorphism with the risk of developing invasive cervical cancer (ICC) from squamous intraepithelial lesions (SILs). METHODS: DNA samples were extracted from peripheral blood cells of 109 patients with squamous intraepithelial lesions (28 low-grade and 81 high-grade cases) and 217 patients with ICC. The CCR2-64I polymorphism was analyzed through polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) (BseJI). The odds ratio (OR) and its 95% confidence interval (CI) were calculated as a measure of the association between CCR2-64I genotypes and cervical cancer risk. RESULTS: The frequency of the G/A genotype was significantly higher in SIL patients (n = 109) than ICC patients (n = 217) (P = 0.005; OR = 0.42; 95% CI: 0.22-0.83). Furthermore, no association was found when we analyzed the influence of the A allele in the progression from low-grade SIL (LSIL) to high-grade SIL (HSIL) (OR = 1.05; 95% CI = 0.370-2.98; P = 0.930), but a statistically significant association was found in the progression from high-grade SIL to ICC (OR = 0.435; 95% CI = 0.222-0.854; P = 0.014). CONCLUSION: These findings suggest that CCR2-64I polymorphism might have a protective role in the evolution from high-grade SIL to ICC.
Abstract: BACKGROUND: Epidemiologic studies have suggested that environmental factors and diet are important risk factors in the pathogenesis of prostate cancer. The N-acetyltransferases (NAT) are important enzymes in activation and inactivation of various carcinogens, including those found in well-cooked meat and cigarette smoke. METHODS: We analyzed DNA samples from 146 prostate cancer patients and 174 healthy men. We used PCR-RFLP method to analyze NAT 1 and NAT 2 polymorphisms. RESULTS: We did not find statistically significant differences in NAT 1 genotypes frequencies between prostate cancer patients and control group. We observed an association of the slow acetylator genotype, NAT 2*6/NAT2*6 with prostate cancer protection (P=0.017; OR=0.31, 95% CI 0.11--0.84). Multivariate logistic regression analysis confirmed this association (0.030; OR=0.32, 95% CI 0.12--0.89). CONCLUSIONS: Our results indicate a role of NAT2 polymorphisms in the carcinogenic pathway of prostate cancer, specifically in a population of Southern Europe.
Abstract: High-risk human papillomavirus are essential for the development of cervical cancer; however, TP53 is the most frequently altered tumor suppressor gene among tumors and is described as a cofactor for cervical carcinogenesis. TP53 has two common polymorphic forms encoding either proline or arginine, at position 72, and the presence of homozygous arginine has been reported as a risk factor for cervical cancer in many populations. We evaluated the effect of this TP53 polymorphism in a northern Portuguese population. We analyzed blood samples of 385 women; 20 with low-grade squamous intraepithelial lesion (SIL), 56 with high-grade SIL, 164 with invasive cervical cancer, and 145 healthy controls, using allele specific-polymerase chain reaction methodology. We observed an increased frequency of the Arg/Arg genotype in the cancer group, but no statistical significance was found between cases and controls (P>0.05). Our results indicate that there is no association between the presence of the Arg allele in codon 72 of TP53 polymorphism and risk of cervical cancer in our population.
Abstract: Human papillomavirus (HPV) plays a major role in the etiology of cervical cancer. However, a complex correlation between viral and cellular genes is necessary for cell cycle control deregulation in the progression to invasive cervical cancer (ICC). Cyclin D1 (CCND1) is an important positive regulator of the G1/S phase of the cell cycle. The CCND1 gene is located at 11q13 and is often altered in human cancers. We analyzed the A870G CCND1 polymorphism by polymerase chain reaction/restriction fragment length polymorphism analysis in 246 women including 50 cases with high-grade squamous intraepithelial lesions of the cervix (HSIL), 93 with ICC, and 103 healthy women. The GG genotype was associated with a 4.32-fold higher risk for the development of HSIL [adjusted odds ratio (aOR)=4.32, 95% confidence interval (CI) 1.50-12.46, P=0.0067), and a 3.26-fold increased risk for the development of ICC (aOR=3.26, 95% CI 1.42-7.53, P=0.006). The proportion of cervical cancer cases attributable to the GG CCND1 genotype was 17.26%. This study indicates that the A870G CCND1 polymorphism could act as a cofactor of HPV in the initiation of cervical carcinogenesis, particularly in the transformation zone of HPV-infected women, supporting evidence for a genetic factor in ICC risk.
Abstract: Cervical cancer is a complex and multifactorial disease. Although there are substantial data supporting the causative role of persistent human papillomavirus (HPV) infection in the development of cervical cancer, the complete course of the disease has never been completely understood. Several risk cofactors have been suggested with controversial results. Portugal has the highest incidence of squamous cell carcinoma (SCC) within western Europe and there are no known studies regarding the role of cofactors in SCC. The aim of our study was to evaluate the role of smoking, sexual behaviour, reproductive and contraceptive history, in the time-to-onset (TTO) of severe cervical lesions (HGSIL/SCC) in the Portuguese population. We verified that age of first sexual intercourse under 18 years (odds ratio (OR) 2.8), pregnancy (OR 2.9), first pregnancy under 21 years (2.6), number of pregnancies (OR 2.3-5.4) and parity (OR 1.9-5.7) are risk factors in the development of cervical neoplasia. Smoke exposure index (SEI) was significantly different (P=0.002) between cases and controls. Our results regarding time-to-onset demonstrate that smoking (P<0.001, log rank test), number of sexual partners (P<0.001, log rank test) and use of oral contraceptives (P<0.001, log rank test) are important determinants in the earlier onset of severe cervical lesions. Using this approach, our findings may help to clarify the role of smoking and other cofactors in the persistence and progression of cervical lesions.
Abstract: Cervical cancer is initiated by high-risk human papillomaviruses (HPV-16 and HPV-18), but an effective immune response may control the progression of this disease. Tumor necrosis factor-alpha (TNF-alpha) is a pro-inflammatory cytokine, that has been implicated in several cancers. In a case-control study, we evaluated the association between the G-308A TNF-alpha promoter polymorphism and the risk for invasive cervical cancer (ICC). TNF-alpha polymorphism was analyzed by PCR-RFLP and confirmed by sequencing. DNA was obtained from blood samples of 439 individuals, including 195 patients with ICC and 244 normal healthy controls. According to our results, women carrying the A allele present a twofold increased risk of developing ICC (p=0.006; OR=1.88; 95% CI [1.20-2.94]). In conclusion, our study suggests that the presence of the high producer allele -308A in the TNF-alpha gene appears to be associated with an increased risk for the development of ICC.
Abstract: A relevant clinical problem in the treatment of ovarian cancer (OC) is the development of resistance to chemotherapy, frequently due to genetic variations in enzymes and receptors. Changes in the HER2 receptor have been associated with breast and ovarian cancers. The role of a polymorphism in the HER2 gene in the clinical outcome of OC patients was investigated in this study. We characterized DNA samples from 111 patients with OC treated with cisplatin and paclitaxel, using PCR-RFLP. Our results indicate that patients carrying the valine homozygotic genotype present a lower overall survival mean, suggesting a role for this polymorphism in the outcome of ovarian cancer patients. The G allele has been implicated in the formation of active HER2 receptors, with a more aggressive phenotype. We hypothesize that HER2 genotypes can be predictive biomarkers in ovarian cancer, contributing to a genetic individual profile of great interest in clinical oncology.
Abstract: Angiotensin-converting enzyme (ACE) degrades vasodilator kinins and generates angiotensin II (Ang II). It has been reported that ACE is synthesized by the prostate and that the AT-1 receptor subtype is the predominant prostatic Ang II receptor. A polymorphism in the human ACE gene has been described and the highest levels of circulating and tissue ACE activity are found in carriers of the DD genotype. In the present study, ACE genotypes were determined in 170 patients with prostate cancer and their association with disease progression was analysed. It was found that the DD genotype was present in 31 of 78 (39.8%) patients with advanced disease and in 19 of 82 (23.2%) with localized disease: this difference was statistically significant (OR = 2.18, 95% CI = 1.11-4.03; p = 0.024). Step-wise logistic regression analysis was used to identify predictive parameters of advanced disease and it was observed that the DD genotype (p = 0.002, OR = 5.4, 95% CI = 1.84-16.06), high-grade tumour (p < 0.001, OR = 8.04, 95% CI = 3.03-21.33), and high serum PSA (p < 0.001, OR = 10.87, 95% CI = 4.06-29.13) were significantly associated with advanced disease. The results of this study support the hypothesis that genetic factors related to ACE may influence the behaviour of human prostate cancer.
Abstract: Endometrial carcinoma is one of the most common gynecological malignancies. Most cases are diagnosed in older patients with diabetes, hypertension, or obesity. The renin-angiotensin system (RAS) has a central role controlling blood pressure and sodium homeostasis. RAS polymorphisms have been reported as genetic determinants of essential hypertension. The objective of this study was to analyze angiotensin I-converting enzyme gene insertion/deletion polymorphism and endometrial human cancer in normotensive and hypertensive women. The presence of an angiotensin converting enzyme (ACE) polymorphism was analyzed by polymerase chain reaction in DNA isolated from peripheral blood samples of 171 women: 70 cases with endometrial cancer (age, 63.6 +/- 9.5 years) and 101 normal control women (age, 61.3 +/- 6.4 years). We detected DD genotype in 47.5%, ID genotype in 44.3%, and II genotype in 8.2% of cases. The allele frequency was 0.69 for D allele and 0.30 for I allele. In normotensives, we found that the presence of I allele (genotypes ID and II) is significantly associated to an earlier age (56.0 +/- 10.1 versus 65.8 +/- 9.9) of onset of endometrial carcinoma (P=0.029). We observed that normotensive women carriers of an allele I have a higher risk of development of endometrial cancer under the age of 63 years (odds ratio=3.60, 95% confidence interval=1.03-12.56; P=0.037). Our findings suggest that ACE polymorphism may be associated with the development of endometrial carcinoma and with the onset of this tumor in younger women. The definition of a pharmacogenomic profile of human neoplasia may help to identify targets for the development of therapeutic or chemoprevention strategies.
Abstract: The genes coding for separate isoforms of both the human glutathione-S-transferase class (GST) mu and class theta enzymes (GSTM1 and GSTT1) are polymorphic with a percentage of normal individuals exhibiting a homozygous deletion of the genes. An association between glutathione, proliferation and tumour angiogenesis has been observed. The aim of the present study was to analyse GST polymorphisms and to determine its correlation with the angiogenesis status of the tumoral tissue of patients with breast cancer. For each case, immunohistochemistry of tumour tissue and DNA genotyping by PCR on genomic DNA isolated from blood cells were performed. The mean intratumoral microvessel density (MVD index) was higher for the cases with GSTM1 wild-type genotype in comparison with the cases with the GSTM1-null genotype (89.6 +/- 10.0 vs. 60.9 +/- 6.7; P = 0.022). This was even more evident for women with a breast cancer onset before the age of 35 (106.9 +/- 11.9 vs. 61.8 +/- 9.8; P =0.011). Multivariate logistic regression analysis of GSTM1 and GSTT1 genotypes, histologic grade, axillary node status and age at diagnosis demonstrate the independent association between GSTM1 genotypes and angiogenesis and the association of GSTM1 -wild type genotype with high MVD index (adjusted OR = 5.98, 95% CI 1.28-28.10, P = 0.023). A role of this enzyme in the hypoxia-induced metabolic pathway can be a connection for its association with angiogenesis. Further studies on the enzymatic components of the glutathione biosynthetic pathway in other cancers could define a pharmacogenomic profile of human neoplasia and help identify targets for the development of therapeutic strategies.
Abstract: BACKGROUND: Glutathione S-transferase (GST) metabolic enzymes may be involved in the development of human cancer. Genetic polymorphisms have been reported in GSTM1, GSTM3, and GSTT1 with functional alterations and influencing cancer risk. METHODS: We analyzed DNA samples from 335 (670 alleles) unrelated individuals, 185 community control subjects, and 150 prostate cancer (PC) patients, for GSTM1, GSTM3, and GSTT1 genotypes using polymerase chain reaction (PCR). RESULTS: The analysis of the frequencies from the 670 alleles indicates that men carrying two B-alleles (GSTM3) have increased risk for PC (OR = 5.50, 95% confidence interval (CI) 1.2-25.8; P = 0.016). Multivariate logistic regression analysis confirmed this association (OR = 5.2, 95% CI 1.1-25.0; P = 0.036). No increased PC risk was observed for men carrying any of the GSTM1 or GSTT1 genotypes (OR = 1.20, 95% CI 0.75-1.90; P = 0.420 for GSTM1 null and OR = 0.87, 95% CI 0.50-1.51; P = 0.550 for GSTM1 null). However, GSTT1 null was overrepresented in men with advanced PC disease (P = 0.038). CONCLUSIONS: Our results indicate that polymorphism in the GSTM3 may be an important biomarker for PC risk, especially in the definition of the genetic risk profile of populations of southern Europe.
Abstract: Leptin's relation with obesity has been clearly demonstrated while its role in oncobiology is still largely unknown. Epidemiological studies on serum leptin provide valuable though controversial data, while in vitro studies consistently show leptin's angiogenic and proliferative potential in cancer. Leptin's activity is mediated by tissue-specific receptors, differentially expressed in organs such as the prostate. The molecular cascades triggered by leptin result in prostatic cell proliferation and angiogenic activity, thus linking the hormone mainly to prostate cancer prognosis. This review also addresses leptin's metabolic interactions with cytokines, growth factors or hormones, establishing perceptive pathways leading to carcinogenesis or prostate cancer progression and metastasis. Better understanding of these mechanisms may help in the development of new and more effective treatments for prostate cancer. The consolidation of leptin molecular genetics profile in prostate cancer patients may help to create susceptibility groups in normal individuals, facilitating a preventive dietary intervention or strategies for chemoprevention. We hypothesize that the balance between androgen and leptin levels may facilitate the increase in the ratio of androgen-independent prostate cancer cells to androgen-dependent cells in the tumour.
Abstract: Infection with human papillomaviruses (HPV) is essential in the carcinogenesis of the uterine cervix. However, a complex interrelation between viral and cellular genes is necessary for cell-cycle control deregulation and development and progression of cervical cancer induction. The TP73 gene is localized in 1p36.3 band, which is often deleted by loss of heterozygosity (LOH) in human cancers. We analyzed the p73 cytosine thymine polymorphism and LOH in this locus by polymerase chain reaction restriction fragment length polymorphism in 134 DNA samples from biopsies of 67 primary untreated invasive cervix tumors and the corresponding peripheral blood. Genotype frequencies of 56.7% for homozygous genotype GC/GC and 43.3% for heterozygous genotype GC/AT were found. The presence of the GC/AT genotype in tumors was associated with lower age at menarche (P=0.039) and high parity (P=0.015). In 20.0% of DNA tumor samples, the AT allele was lost compared with their DNA normal blood pairs. The AT allele was conserved in women with high parity. This was not the case in the group with low parity, with 33.3% of patients showing loss of the AT allele in tumor DNA (P=0.041). These results suggest that TP73 genetic alterations may contribute to the genesis and/or progression of cervical carcinoma in an HPV-infected transformation zone under prolonged exposure to events related to pregnancy.
Abstract: BACKGROUND: Leptin has been consistently associated with angiogenesis and tumoral growth. A G/A single nucleotide polymorphism (SNP) at the -2548 site in leptin gene (LEP) is associated with overexpression of leptin (A-allele). METHODS: We evaluated DNA samples from 268 (536 alleles) unrelated individuals, 118 healthy controls (HCs) and 150 prostate cancer (PC) patients, for leptin gene (LEP) locus -2548 genotypes. RESULTS: We found an overrepresentation of the A-allele in PC patients and that there is a significantly higher risk for PC among A carriers (OR = 1.60; confidence interval (CI), 1.13-2.28, P = 0.008). Linear trend analysis showed that quantitative increase of A-allele presence was associated with significantly higher risk for PC (P = 0.003) in heterozygous (OR = 2.11; CI, 1.20-3.71) and homozygous (OR = 2.93; CI, 1.27-6.75) genotypes. Furthermore, the AA and AG genotypes represent significantly higher risk (OR = 4.67; CI, 1.69-12.88 and OR = 2.58; CI, 1.19-5.58, respectively) for advanced disease. CONCLUSIONS: According to our results we hypothesize that the polymorphism in LEP gene may be relevant to PC risk and progression, supporting the hypothesis for leptin involvement in cancer ethiopathogenesis.
Abstract: Breast cancer is a major public health problem around the world, and its carcinogenesis is not yet well understood. The human epidermal growth factor Receptor 2 (HER2) seems to play an important role in the development of this neoplasia, and genetic alterations in this gene, such as point mutations and polymorphisms have been detected in breast cancer patients. We analysed the frequency of a single nucleotide polymorphism in the HER2 gene in blood samples from 152 breast cancer patients and 146 healthy controls using the polymerase chain reaction methodology, followed by restriction fragment length polymorphism (PCR-RFLP). We found a twofold increase in risk of breast cancer in women who are carriers of a Val allele genotype-Ile/Val and Val/Val genotypes [odds ratio (OR)=2.00; 95% confidence interval (CI) 1.23-3.25; P=0.005]. Our results indicate an association between the presence of the Val allele in the HER2 polymorphism and the risk of breast cancer. Further studies are needed to evaluate the role of this polymorphism in the behaviour of breast cancer.
Abstract: 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.
Abstract: Several genetic alterations have been associated with sporadic prostate cancer (PCa). In this study, the association between RsaI and DraI polymorphisms of CYP2E1 and PCa risk was analysed in a case-control study of 227 individuals using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Regarding DraI polymorphisms, the DD genotype is over-represented in PCa cases when compared with the control group (odds ratio (OR) 2.12; 95% confidence interval (CI) 1.11-4.05; P=0.022). Regarding the RsaI polymorphism, no significant differences were found. The results of this study indicate that DraI polymorphisms of the CYP2E1 gene may be associated with a twofold increased risk for the development of PCa.
Abstract: 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.
Abstract: Steroid hormones and their receptors are involved as initiators or promoters in prostate carcinogenesis. The intrauterine-perinatal period and maternal estrogen and testosterone levels have been proposed to be of etiologic importance in prostate tumorigenesis and cancer progression. The objective of this study was to analyze genetic polymorphisms in the androgen receptor ARStuI by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and in the estrogen receptor ER325 by PCR-single-strand conformational polymorphism (PCR-SSCP). In our study of 170 prostate cancer patients, ARStuI and ER325 genotypes and their association with disease progression and metastasis were analyzed. Age-adjusted logistic regression analysis indicates the association of ARStuI S1 allele with high-grade tumor (P = 0.033; OR = 3.0, 95% CI = 1.1-8.3) and the association of ER325 with high-grade tumor (P = 0.003; OR = 3.0, 95% CI = 1.4-6.4), advanced disease (P = 0.020; OR = 2.4, 95% CI = 1.1-5.1), risk of progression (P = 0.027; OR = 2.5, 95% CI = 1.1-5.7) and the presence of metastatic disease (P = 0.006; OR = 3.1, 95% CI = 1.4-6.8). In summary, this study has demonstrated androgen receptor (ARStuI) and estrogen receptor (ER325) genetic polymorphisms in prostate cancer patients and its association with disease progression and metastasis. Our results support the hypothesis that genetic factors related to steroid hormone receptors may influence the behavior of human prostate cancer.
Abstract: The endothelial cell-specific form of nitric oxide synthases (ecNOS) is localized at 7q35-q36 and is involved in vascular development and tumour growth in human prostate cancer. We have conducted a case-control study to investigate the prevalence of two polymorphisms at intron 4 (ecNOS4a/b) and exon 7 (Glu-Asp298) of ecNOS gene in 125 prostate cancer (PCa) patients and in 153 controls. We observed that the a-allele (aa or ab genotypes from ecNOS4a/b) was over-presented in the group of PCa with Gleason histological grade >or=7 (P=0.041). With regard to the Glu-Asp298 polymorphism, patients with the T-allele were younger than patients with no T-allele (P=0.037), and a statistically significant difference was noted in the Glu-Asp298 genotype distribution between cases with advanced disease and cases with localized disease (P=0.0013). When comparing cases and controls with logistic regression analysis we observed that the presence of the a-allele is associated with prostate cancer risk (odds ratio (OR) 1.83; 95% confidence interval (CI) 1.06-3.17; P=0.029), to high histological grade (Gleason >or=7) of PCa (OR 2.18; 95% CI 0.95-4.98; P=0.062) and with the risk of progression of the cancer disease (OR 2.85; 95% CI 1.19-6.82; P=0.018). Furthermore, we found that carriers with the combination of the a-allele (aa and ab ecNOS4a/b genotypes) and T-allele (GT and TT from Glu-Asp298) have a threefold increase in prostate cancer risk (OR 3.13; 95% CI 1.41-6.91, P=0.004). In summary, we have identified an NO-related genetic risk factor for prostate cancer that may help in understanding the molecular mechanism involved in the individual susceptibility to prostate cancer.
Abstract: 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.
Abstract: Breast cancer is the most frequent neoplasm in women. Expression of the estrogen receptor (ER) has a key role in breast cancer; the ER gene is located at chromosome 6q24-q27 and is made up of 8 exons with a total of 140 kb. The polymorphism in codon 325 of exon 4 (ER325) is a transition CCC-->CCG. The objective of this study is to analyze the frequency of this polymorphism in breast cancer using the polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) technology. DNA was extracted from tumor cells of 70 breast cancer patients and from the peripheral blood of 69 individuals without any known pathology (control group). Amplification products of the ER gene were analyzed by SSCP. In breast cancer patients the ER325 polymorphism was detected in 42.8% of the cases. In contrast, in the control group, the frequency of the same polymorphism was 24.6. Statistical comparison of the frequency distributions revealed that they are significantly different (p = 0.023). There was also an association between ER325 polymorphism and the absence of lymph node metastases (p = 0.038). Our data suggest that there is a relationship between the ER325 polymorphism and susceptibility to breast cancer (OR = 2.3; 1.10 < OR < 5.1) and that it can also be related with the metastasization process.
Abstract: 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.
Abstract: 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.
Abstract: 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.
