Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GSTP1 and GSTM1 are genes involved in Phase II metabolism, whereas p53 is a tumor suppressor gene. Individually, functional polymorphisms of these genes have been studied as risk factors for lung cancer. Small sample sizes have hindered the detection of possible increases in risk associated with having two or more "at risk" polymorphisms of these three genes. In a large Caucasian population, we examined the association of combined variant genotypes [or double-variants (DVs)] of these three genes and lung cancer risk, compared with their corresponding "double-wild-type" genotypes. Because these DVs may promote lung carcinogenesis at an earlier age, a subgroup of individuals aged 55 years or younger was examined separately. Using a case-control design, individuals were genotyped for GSTM1, GSTP1, and p53 codon 72 using PCR-RFLP techniques. All of the analyses used multiple logistic regression. Indicator variables were created to evaluate the risk for individuals with the following DVs: GSTP1 GG + GSTM1-null and GSTP1 GG + p53 Arg/Pro or Pro/Pro. A total of 1694 cases and controls were evaluated. In the whole population, those with the double variants have a higher risk of lung cancer when compared with those with the double-wild-type genotypes, supporting our original hypothesis. Individuals with the GSTP1 and GSTM1, DV (P1-M1 DV) had a marginally significant higher risk of lung cancer compared with their double-wild-type counterparts [adjusted odds ratio (AOR), 1.60; 95% confidence interval (CI), 0.95-2.70]. A significantly higher risk was found for the GSTP1, p53 DV (P1-p53 DV; AOR, 1.99; 95% CI, 1.12-3.53). Among individuals aged 55 or younger, these risks were even higher: for the P1-M1 DV the AOR was 4.03 (95% CI, 1.47-11.1); for the P1-p53 DV the AOR was 5.10 (95% CI, 1.42-18.30). Specific DVs of GSTM1, GSTP1, and p53 codon 72 are associated with a higher lung cancer risk. This susceptibility is highest among younger individuals.
 ...
PMID:Combinations of the variant genotypes of GSTP1, GSTM1, and p53 are associated with an increased lung cancer risk. 1201 59

Somatic genetic alterations in tumors are known to correlate with survival, but little is known about the prognostic significance of germ-line variation. We assessed the effect of germ-line variation on survival among women with breast cancer participating in a British population-based study. Up to 2430 cases for whom current vital status data were available were screened for BRCA1/2 mutations and genotyped for polymorphisms in 22 DNA repair, hormone metabolism, carcinogen metabolism, and other genes. The effect of genotype on outcome was assessed by Cox regression analysis. The largest effect was observed for the silent polymorphism D501D (t>c) in LIG4, a gene involved in DNA double-strand break repair. The estimated hazard ratio (HR) in cc homozygotes relative to tt homozygotes was 4.0 (95% confidence interval, 2.1-7.7; P = 0.002), and this effect remained after stratification by stage, grade, and tumor type [HR, 4.2 (1.8-9.4); P = 0.01]. Total length of a CYP19 IVS4 (ttta)(n) repeat was also associated with survival [HR, 0.9 (0.8-1.0); P = 0.01], but this became nonsignificant after stratification by stage, grade, and tumor type. Poorer survival was observed for 10 BRCA1 mutation carriers [HR, 4.1 (1.3-13); P = 0.047]; however, after adjustment for known prognostic factors, the HR estimate decreased to 2.0 and became nonsignificant (P = 0.4). CYP17 (P = 0.05) and TP53 (P = 0.06) polymorphisms showed marginally significant associations in unstratified analyses. No effect on survival was seen for polymorphisms in ATM, BRCA1/2, CHK2, KU70, NBS1, RAD51, RAD52, XRCC3, AR, COMT, NQO1, VDR, ADH3, CYP1A1, GSTP1, TGF-beta, or CDH1. Even if confirmed, the prognostic markers identified in this study are unlikely to replace current markers of prognosis such as estrogen receptor status. However, our results demonstrate the potential of the analysis of germ-line variation to provide insight into the biological determinants of response to treatment and prognosis in breast cancer.
 ...
PMID:Effect of germ-line genetic variation on breast cancer survival in a population-based study. 1203 13

DNA adducts associated with tobacco smoking could provide a marker of biologically effective dose of tobacco carcinogens and improve individual cancer risk prediction. A significant number of clinical and epidemiologic studies have reported associations of increased DNA adduct levels with the occurrence of the prevalent tobacco related cancers including cancer of the lung, head and neck, and bladder. The inducibility of DNA adducts following in vitro treatments using blood lymphocytes also appears to be a risk factor in the development of lung and head and neck cancer. Corroborative evidence pointing to the importance of DNA adducts in tobacco carcinogenesis include numerous studies showing associations of tobacco smoke exposure with the induction of DNA adducts in humans in vivo. Further effort is necessary, however, to more fully characterize the dose-response relationship between smoking and DNA adducts in exposed target and surrogate tissues. The relationship between gene polymorphisms thought to modify tobacco-related cancer risk and DNA adduct levels is complex. Results of some DNA adduct studies (both in vitro and in vivo) appear inconsistent with the epidemiologic findings. This is evident for polymorphisms involving both carcinogen metabolism (e.g. GSTP1) and DNA repair (e.g. XRCC1). Molecular studies of human tumors suggest associations of p53 mutation with DNA adducts and have revealed correlations of DNA adduct levels with somatic alterations (e.g. 3p21 LOH) that are thought to occur at the very earliest stages of tobacco carcinogenesis. More research is needed to assess the relationship between endogenous sources of DNA adducts and tobacco smoke exposure and the relative oncogenic effects of chemically stable versus unstable DNA adducts. Many potentially fruitful new avenues of cancer research are emerging that integrate DNA adduct analyses with assessments of smoking, genetics, diet and ambient air quality. These investigations aim to understand the multifactorial nature of interindividual variability in response to tobacco carcinogens. As these trends continue a variety of innovative study designs and approaches will become important in human populations.
 ...
PMID:DNA adduct burden and tobacco carcinogenesis. 1237 80

Promoter hypermethylation represents a primary mechanism in the inactivation of tumor suppressor genes during tumorigenesis. To determine the frequency and timing of hypermethylation during carcinogenesis of astrocytic tumors, we analysed promoter methylation status of ten tumor-associated genes (MGMT, GSTP1, DAPK, p14ARF, THBS1, TIMP-3, p73, p16INK4A, RB1 and TP53) in a series of 88 astrocytic gliomas, including 24 diffuse astrocytomas; 21 anaplastic astrocytomas, and 43 glioblastomas (33 primary and 10 secondary), as well as two non-neoplastic brain samples, by methylation-specific PCR. Aberrant CpG island methylation was detected in all ten genes analysed, and all but one sample displayed anomalies in at least one gene. The methylation index (number methylated genes/total genes analysed) was 0.3, 0.38, 0.33 and 0.29 for diffuse astrocytomas, anaplastic astrocytomas and secondary and primary glioblastomas, respectively. Some differences may be established regarding the methylation profiles of specific genes and tumor types: MGMT, THBS1, TIMP-3, and p16INK4A appear hypermethylated in low-grade tumors (at least in 45% of cases), whereas GSTP1, DAPK, and p14ARF are mostly changed in 15-50% of the higher grade forms versus <10% in low-grade tumors. Some variation also exists regarding the methylation values for p73 and RB1 (10-40% of cases) among all groups. TP53 presented hypermethylation rates <10% in all tumor subtypes. Our findings thus suggest that methylation represents a common mechanism that contributes to inactivating cancer-related genes in astrocytic neoplasms. This epigenetic change is, in general, an early event in the development of astrocytic neoplasms but this gene silencing mechanism may also appear as a late event involving some loci.
 ...
PMID:Promoter hypermethylation of multiple genes in astrocytic gliomas. 1257 14

The objectives of this exploratory case-control study were to evaluate whether genetic polymorphisms of selected Phase I and II metabolizing enzymes are associated with the risk of developing primary esophageal adenocarcinoma, and to investigate potential associations between genotypes and p53 tumor suppressor gene alterations. Cases comprised 45 patients with surgically resected esophageal adenocarcinomas, defined according to strict clinico-pathologic criteria. PCR-based assays (RFLP/SSCP) were used to genotype cytochrome P450 (CYP) 1A1 [MspI; Ile:Val], microsomal epoxide hydroxylase (mEH) (fast and slow alleles), and glutathione S-transferase (GST) T1, M1 and P1. Healthy controls (n=45) from the same geographic region were matched for age, gender and smoking history. For GSTP1, the Ile/Val (a/b) and Val/Val (b/b) variants were seen at increased frequency in cases compared to controls (49% versus 27% and 15% versus 9%, respectively), although these differences achieved only borderline statistical significance (P=0.09). For mEH (exon 3), the presence of the Tyr polymorphism (slow allele) was reduced in cases (42%) compared to controls (53%; P=0.05). Predicted high mEH activity was seen more frequently in cases than controls (OR, 2.2; 95% CI, 0.7-7.3). Polymorphism frequencies for GSTT1, GSTM1, and CYP1A1 were not statistically different between cases and controls. Cases with the GSTT1 null genotype had tumors with altered p53 more frequently than did cases with the common form of GSTT1 (25 versus 6%, respectively; P=0.08). We conclude that polymorphisms of GSTP1 and mEH may be implicated in individual susceptibility to esophageal adenocarcinoma, possibly as a result of increased Phase I activation (mEH) and impaired Phase II detoxification (GSTP1). GSTT1 may also play a role in esophageal tumorigenesis through a pathway that involves abnormalities in the p53 tumor suppressor gene.
 ...
PMID:Associations between genetic polymorphisms of Phase I and II metabolizing enzymes, p53 and susceptibility to esophageal adenocarcinoma. 1267 May 26

Aberrant methylation of CpG islands located in promoter regions represents one of the major mechanisms for silencing of cancer-related genes in tumour cells. We determined the frequency of aberrant CpG island methylation of several tumour-associated genes: MGMT, GSTP1, DAPK, p14ARF, THBS1, TIMP-3, p73, p16INK4A, RB1 and TP53 in 24 neurogenic tumours consisting of pilocytic astrocytomas (n=13) and medulloblastomas (n=11). The methylation index (number methylated genes/total genes analysed) displayed slight differences (0.18 and 0.25, respectively), and the profile of methylated genes in the two neoplasms was distinct, as predicted. The main differences involved the methylation rate of GSTP1 (0% in pilocytic astrocytomas vs. 18% medulloblastomas) and p14ARF (0% in pilocytic astrocytomas vs. 45% in medulloblastomas) genes. Pilocytic astrocytomas also demonstrated some differences when compared to methylation data from other astrocytic tumours, primarily regarding the MGMT methylation rate. Despite the fact that these differences do not show specific tumour-associated gene methylation patterns, our findings should help us understand the pathogenic mechanisms of both neurogenic neoplasm types.
 ...
PMID:Epigenetic changes in pilocytic astrocytomas and medulloblastomas. 1268 7

Oxidative stress and resulting lipid peroxidation are important risk factors for dietary-associated colon cancer. To get a better understanding of the underlying molecular mechanisms, we need to characterise the risk potential of the key compounds, which cause DNA damage in cancer-relevant genes and especially in human target cells. Here, we investigated the genotoxic effects of 4-hydroxy-2-nonenal (HNE) and hydrogen peroxide (H(2)O(2)) in human colon cells (LT97). LT97 is a recently established cell line from a differentiated microadenoma and represents cells from frequent preneoplastic lesions of the colon. The genomic characterisation of LT97 was performed with 24-colour FISH. Genotoxicity was determined with single cell microgelelectrophoresis (Comet assay). Comet FISH was used to study the sensitivity of TP53-a crucial target gene for the transition of adenoma to carcinoma-towards HNE. Expression of glutathione S-transferases (GST), which deactivates HNE, was determined as GST activity and GSTP1 protein levels. LT97 cells were compared to primary human colon cells and to a differentiated clone of HT29. Karyotyping revealed that the LT97 cell line had a stable karyotype with only two clones, each containing a translocation t(7;17) and one aberrant chromosome 1. The Comet assay experiments showed that both HNE and H(2)O(2) were clearly genotoxic in the different human colon cells. HNE was more genotoxic in LT97 than in HT29clone19A and primary human colon cells. After HNE incubation, TP53 migrated more efficiently into the comet tail than the global DNA, which suggests a higher susceptibility of the TP53 gene to HNE. GST expression was significantly lower in LT97 than in HT29clone19A cells, which could explain the higher genotoxicity of HNE in the colon adenoma cells. In conclusion, the LT97 is a relevant model for studying genotoxicity of colon cancer risk factors since colon adenoma are common preneoplastic lesions occurring in advanced age.
 ...
PMID:Human adenoma cells are highly susceptible to the genotoxic action of 4-hydroxy-2-nonenal. 1271 79

Allele frequencies are rather constant among different ethnic groups in many genetic polymorphisms, but some polymorphisms vary in the allele frequency depending on the time when the germ-line base exchanges occurred in the history of humans and on the adaptability of the phenotypes to given environment. This review documented the allele frequencies of polymorphisms pertaining to cancer risk for Japanese, Koreans, and Chinese. Twenty-five polymorphisms of 21 genes whose allele frequencies were available for at least two out of the three ethnic groups were selected. They were ALDH2 Glu487Lys, COMT Val158Met, CYP1A1 MspI and Val/Ile, CYP1B1 Leu432Val, CYP2E1 RsaI, CYP17 T-34C, ER C975G, GSTM1, GSTT1, GSTP1 Ile105Val, IL-1B C-511T, IL-1RN 86-bp VNTR (variable number of tandem repeats), MTHFR C677T and A1298C, NAT1, NAT2, NQO1 Pro187Ser, OGG1 Ser326Cys, p21 Ser31Arg, p53 Arg72Pro, TNF-A G-308A and G-238A, and XRCC1 Arg194Trp and Arg399Gln. The allele frequencies were found for 24 in Japanese, 16 in Koreans, and 24 in Chinese. All of the polymorphisms had similar allele frequencies for these ethnic groups, except the following polymorphisms; ALDH2 Glu487Lys whose Lys allele was more common for Japanese and Taiwanese, COMT Val158Met whose Met allele was more common for Japanese, and NAT2 rapid/slow whose slow alleles were more common for Chinese. When compared with the allele frequencies among Caucasians, the following minor alleles were more frequent among Japanese/Koreans/Chinese; ALDH2 478Lys, CYP1A1 m1 and m2, CYP2E1 c2, ER 975G, GSTT1 null, NAT1 *10, NQO1 187Ser, OGG1 326Cys, p21 31Arg, and XRCC1 194Trp, and less frequent in COMT 158Met, GST-P1 105Val, IL-1RN non-4R, MTHFR 1298C, and TNF-A -308A. The differences in genetic background may affect the impact on the lifestyle factors and/or genotypes examined in epidemiological studies. However, the influences of the variations in the allele frequency seemed to be limited among Japanese, Koreans, and Chinese. The substantial differences in the allele frequency from Caucasians could modify the influences of lifestyle factors and polymorphism genotypes, resulting in the inconsistent results of epidemiologic studies.
 ...
PMID:Allele Frequencies of 25 Polymorphisms Pertaining to Cancer Risk for Japanese, Koreans and Chinese. 1271 76

Promoter hypermethylation represents a primary mechanism in the inactivation of tumor suppressor genes during tumorigenesis. To determine the frequency and timing of hypermethylation during carcinogenesis of nonastrocytic tumors, we analyzed promoter methylation status of 10 tumor-associated genes in a series of 41 oligodendrogliomas (22 World Health Organization [WHO] grade II; 13 WHO grade III; 6 WHO grade II-III oligoastrocytomas) and 7 WHO grade II-III ependymomas, as well as 2 nonneoplastic brain samples, by a methylation-specific polymerase chain reaction. Aberrant CpG island methylation was detected in 9 of 10 genes analyzed, and all but one sample displayed anomalies in at least one gene. The frequencies of hypermethylation for the 10 genes were as follows, in oligodendrogliomas and ependymomas, respectively: 80% and 28% for MGMT; 70% and 28% for GSTP1; 66% and 57% for DAPK; 44% and 28% for TP14(ARF); 39% and 0% for THBS1; 24% and 28% for TIMP3; 24% and 14% for TP73; 22% and 0% for TP16(INK4A); 3% and 14% for RB1; and 0% in both neoplasms for TP53. No methylation of these genes was detected in normal brain tissue samples. We conclude that a high frequency of aberrant methylation of the 5' CpG island of the MGMT, GSTP1, TP14(ARF), THBS1, TIMP3, and TP73 genes is observed in nonastrocytic neoplasms. This aberration seems to occur early in the carcinogenesis process (it is already present in the low-grade forms), although in some instances (DAPK, THBS1, and TP73) it appears also associated with the genesis of anaplastic forms.
 ...
PMID:Aberrant promoter methylation of multiple genes in oligodendrogliomas and ependymomas. 1285 Mar 76

Aberrant methylation of the promoter CpG island of human genes is an alternative gene inactivation mechanism that contributes to the carcinogenesis of human tumours. We have determined the methylation status of the CpG island of 11 tumour-related genes (RB1, p14ARF, p16INK4a, p73, TIMP-3, MGMT, DAPK, THBS1, caspase 8, TP53 and GSTP1) in 18 neurofibromas (including one plexiform neurofibroma) and three neurofibrosarcomas, as well as two non-neoplastic peripheral nerve sheath samples, using methylation-specific polymerase chain reaction. The series included sporadic and neurofibromatosis type 1-associated tumours. The incidence of aberrant methylation in the tumour samples was 52% for THBS1, 43% for MGMT, 33% for TIMP-3, 19% each for p16INK4a and p73, 14% for RB1, 5% for p14ARF, and 0% for DAPK, caspase 8, TP53 and GSTP1. No methylation of these genes was detected in the two samples of non-neoplastic peripheral nerve sheath. All but three samples in the study displayed aberrant methylation in at least one of the studied genes, and there was no correlation between methylation status and the patients' clinical parameters. These findings suggest that methylation of some tumour-related genes may play a significant role in the tumourigenesis of neurofibromas/neurofibrosarcomas.
 ...
PMID:Aberrant CpG island methylation in neurofibromas and neurofibrosarcomas. 1288 34


<< Previous 1 2 3 4 5 6 7 8 9 Next >>