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

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.
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PMID:Effect of germ-line genetic variation on breast cancer survival in a population-based study. 1203 13

Carcinogens present in tobacco smoke lead to several types of DNA damage in bronchial cells. In lung cancer, karyotype, allelotype, and fluorescence in situ hybridization analyses have demonstrated the common presence of aneuploidy, although its severity varies considerably among tumors. Deficiencies in the DNA-double strand break (DSB) repair system may be critical in the generation and persistence of chromosomal gains or losses during lung tumorigenesis. Therefore, we examined whether specific DSB repair gene polymorphisms were associated with an increase in tobacco-induced DNA damage, including gene mutations (p53 and KRAS) and chromosomal alterations. Nonsynonymous polymorphisms with a frequency higher that 0.1 at the XRCC3, NBS1, and BRCA2 genes were selected for the study. A PCR-RFLP analysis was performed to identify the Met241Thr, Glu185Gln, and Asn372His polymorphisms in the XRCC3, NBS1, and BRCA2 genes, respectively, in 109 lung cancer patients. Interestingly, the prevalence of p53 mutations was significantly greater among individual homozygous for the NBS1-185Gln allele (8 of 8, 100%) than among individuals for the wild-type allele (24 of 52, 46%). This increase in p53 mutation frequency was largely attributable to an increased prevalence of G-->T or C-->A transversions among these patients (P < 0.001). In addition, the association between this type of mutation and the NBS1-185Gln allele remained statistically significant after adjusting for age, smoking, and histological cell-type (odds ratio = 3.42 for heterozygous and odds ratio = 38.3 for NBS1-185Gln homozygous). Germ-line variants in the NBS1 gene may play a role in the lung carcinogenesis in cigarette smokers.
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PMID:Screening of homologous recombination gene polymorphisms in lung cancer patients reveals an association of the NBS1-185Gln variant and p53 gene mutations. 1291 99

We present an oligonucleotide microarray ("MetaboChip") based on the arrayed primer extension (APEX) technique, allowing genotyping of single nucleotide polymorphisms (SNPs) in genes of interest for cancer susceptibility and pharmacogenetics. APEX consists of a sequencing reaction primed by an oligonucleotide anchored with its 5' end to a glass slide and terminating one nucleotide before the polymorphic site. The extension with one fluorescently labeled dideoxynucleotide complementary to the template reveals the polymorphism. Ninety-three SNPs in 42 genes were selected among those resequenced in the context of the SNP500 project, using a set of 102 reference DNA samples from the Coriell Biorepository. Selected SNPs belong to the following genes: ADH1B, ALDH2, APEX, CDKN2A, COMT, CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2C19, CYP2C9, CYP2E1, CYP3A4, DRD2, DRD4, EPHX1, ERCC1, ERCC2, ERCC4, ERCC5, GRPR, GSTA4, GSTM3, GSTP1, GSTT2, LIG3, MDM2, MGMT, MPO, NAT1, NAT2, NQO1, OGG1, PCNA, POLB, SLC6A3, SOD2, TP53, XRCC1, XRCC2, XRCC3, and XRCC9. We assessed the performance of APEX by comparing the results obtained with MetaboChip against those reported by the SNP500. Among 88 SNPs that yielded signals, 6 showed less than 99% of concordance, whereas 82 performed accurately, showing that APEX is a reliable and sensitive genotyping method.
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PMID:Evaluation of a microarray for genotyping polymorphisms related to xenobiotic metabolism and DNA repair. 1457 48

DNA repair genes play a major role in maintaining genomic stability through different repair pathways that are mediated by cell cycle control genes such as p53. We found previously that glioma patients were susceptible to gamma-ray-induced chromosomal breaks, which may be influenced by genetic variation in genes involved in DNA strand breaks, such as XRCC1 in single-strand break repair, XRCC3 and RAD51 in homologous recombination repair, and XRCC7 in nonhomologous end joining double-strand break repair. Therefore, we tested the hypothesis that genetic polymorphisms in XRCC1, XRCC3, RAD51, XRCC7, and p53 were associated with risk of glioma in 309 patients with newly diagnosed glioma and 342 cancer-free control participants frequency matched on age (+/- 5 years), sex, and self-reported ethnicity. We did not find any statistically significant differences in the distributions of XRCC1 Arg399Gln, XRCC3 Thr241Met, RAD51 G135C, and P53 Arg72Pro polymorphisms between the cases and the controls. However, the XRCC7 G6721T variant T allele and TT genotype were more common in the cases (0.668 and 43.4%, respectively) than in the controls (0.613 and 38.9%, respectively), and the differences were statistically significant (P = 0.045 and 0.040, respectively). The adjusted odds ratios were 1.78 (95% confidence interval, 1.08-2.94) and 1.86 (95% confidence interval, 1.12-3.09) for the GT heterozygotes and TT homozygotes, respectively. The combined T variant genotype (GT+TT) was associated with a 1.82-fold increased risk of glioma (95% confidence interval, 1.13-2.93). These results suggest that the T allele may be a risk allele, and this XRCC7 polymorphism may be a marker for the susceptibility to glioma. Larger studies are needed to confirm our findings and unravel the underlying mechanisms.
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PMID:Polymorphisms of DNA repair genes and risk of glioma. 1531 91

Homologous recombination is a double-strand break repair pathway required for resistance to DNA damage and maintaining genomic integrity. In mitotically dividing vertebrate cells, the primary proteins involved in homologous recombination repair are RAD51 and the five RAD51 paralogs, RAD51B, RAD51C, RAD51D, XRCC2, and XRCC3. In the absence of Rad51d, human and mouse cells fail to proliferate, and mice defective for Rad51d die before birth, likely as a result of genomic instability and p53 activation. Here, we report that a p53 deletion is sufficient to extend the life span of Rad51d-deficient embryos by up to 6 days and rescue the cell lethal phenotype. The Rad51d-/- Trp53-/- mouse embryo-derived fibroblasts were sensitive to DNA-damaging agents, particularly interstrand cross-links, and exhibited extensive chromosome instability including aneuploidy, chromosome fragments, deletions, and complex rearrangements. Additionally, loss of Rad51d resulted in increased centrosome fragmentation and reduced levels of radiation-induced RAD51-focus formation. Spontaneous frequencies of sister chromatid exchange were not affected by the absence of Rad51d, but sister chromatid exchange frequencies did fail to be induced upon challenge with the DNA cross-linking agent mitomycin C. These findings support a crucial role for mammalian RAD51D in normal development, recombination, and maintaining mammalian genome stability.
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PMID:Extensive chromosomal instability in Rad51d-deficient mouse cells. 1578 18

Breast cancer is the most frequent cancer in women and represents the second leading cause of cancer death among women (after lung cancer). The etiology of breast cancer is still poorly understood with known breast cancer risk factors explaining only a small proportion of cases. Risk factors that modulate the development of breast cancer discussed in this review include: age, geographic location (country of origin) and socioeconomic status, reproductive events, exogenous hormones, lifestyle risk factors (alcohol, diet, obesity and physical activity), familial history of breast cancer, mammographic density, history of benign breast disease, ionizing radiation, bone density, height, IGF- 1 and prolactin levels, chemopreventive agents. Additionally, we summarized breast cancer risk associated with the following genetic factors: breast cancer susceptibility high-penetrance genes (BRCA1, BRCA2, p53, PTEN, ATM, NBS1 or LKB1) and low-penetrance genes such as cytochrome P450 genes (CYP1A1, CYP2D6, CYP19), glutathione S-transferase family (GSTM1, GSTP1), alcohol and one-carbon metabolism genes (ADH1C and MTHFR), DNA repair genes (XRCC1, XRCC3, ERCC4/XPF) and genes encoding cell signaling molecules (PR, ER, TNFalpha or HSP70). All these factors contribute to a better understanding of breast cancer risk. Nonetheless, in order to evaluate more accurately the overall risk of breast tumorigenesis, novel genetic and phenotypic traits need to be identified.
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PMID:Understanding breast cancer risk -- where do we stand in 2005? 1578 78

Uterine smooth muscle tumors of uncertain malignant potential (STUMPs) are difficult both from the diagnostic and patient management standpoint because they cannot be classified as benign or malignant by conventional histologic criteria. This study's aim was to determine the diagnostic utility of allelic imbalance (AI) analysis in uterine smooth muscle tumors. Using microdissection and genotyping, we tested 5 leiomyomas, 6 STUMPs, and 10 leiomyosarcomas with follow-up for AI across a panel of seven tumor suppressor genes (p16, p21, p53, VHL, XRCC3, RB, and NM-23). None of the 6 patients with STUMP experienced recurrent disease, whereas 8 of the 10 patients diagnosed with leiomyosarcoma died of disease at follow-up. The mean frequency of allelic loss (FAL) for leiomyomas (18%) was not significantly different from that of STUMPs (21%) (P = 1), whereas leiomyosarcomas displayed a significantly higher FAL (52%) than both leiomyomas (P = 0.001) and STUMPs (P = 0.002). Loss of NM-23, a reported tumor metastasis suppressor gene, was found only in leiomyosarcomas (5 of 9, or 56%), and 4 of 5 (80%) of these were the only cases that demonstrated distant metastases (P = 0.04). Additionally, an FAL of >50% correlated with both NM-23 loss (P = 0.008) and distant metastatic disease (P = 0.04). In conclusion, leiomyomas and STUMPs displayed similar mean FALs and all were clinically benign, whereas uterine leiomyosarcomas had significantly higher frequencies of allelic loss than both leiomyomas and STUMPs. Molecular profiling may thus provide a valuable tool in assessment of malignancy in uterine smooth muscle tumors. Additionally, NM-23 is a promising candidate gene for determination of metastatic potential in these tumors.
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PMID:Analysis of allelic loss as an adjuvant tool in evaluation of malignancy in uterine smooth muscle tumors. 1633 Sep 48

We studied the effects of polymorphisms in nine genes involved in DNA repair and detoxification on occurrence and type of p53 mutation in 327 bladder cancer patients. The included polymorphisms are XPC(Lys939Gln), XPD(Lys751Gln), XPG(Asp1104His), XRCC1(Arg3999Gln), XRCC3(Thr241Met), NBS1(Glu185Gln), cyclin D1(Pro241Pro), MTHFR(Ala222Val and Glu429Ala) and NQO1(Arg139Trp and Pro187Ser). We found increased risk for p53 mutation among cyclin D1 variant allele homozygotes (OR 2.4 CI 0.8-6.7). Among non-smokers, 75% (3/4) with p53 mutation but only 12.5% (3/24) without p53 mutations were XRCC3 241Met homozygotes (P=0.03). Among smokers, all p53 transversions (3/3), but only 41.7% (5/12) of p53 transitions were found among carriers of the XPC 939Gln allele. Individuals carrying the NQO1 187Ser allele showed increased risk for p53 transversions (OR 4.7, CI 0.9-26.1). All (2/2) NQO1 139Trp allele carriers but only 17.5% (7/40) of the Arg139 homozygotes had p53 transversions. Our findings suggest that altered repair and detoxification due to genetic polymorphism may influence the occurrence of p53 mutations in bladder cancer.
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PMID:Influence of polymorphism in DNA repair and defence genes on p53 mutations in bladder tumours. 1634 42

We investigated if the presence of single nucleotide polymorphisms (SNPs) in the XRCC1, XRCC3, and XPD genes were associated with the type and frequency of p53 mutations in bladder cancer. Using a hospital-based case-control study we have previously reported risks for the XRCC1 codon 194, XRCC1 codon 399, XRCC3 codon 241, and XPD codon 751 SNPs 1-3. We have also previously reported mutation data for 149 cases from this study who were screened for mutations in exons 4 through 9 of the p53 gene 4. Here we investigate possible associations between the DNA repair SNPs mentioned above and the presence of p53 mutations by comparing the frequency of each genotype between p53 mutation positive and negative cases. We also considered different classes of p53 mutations, including any mutation (nonsense, missense or silent), transversions and transitions and estimated odds ratios (ORs) and 95% confidence intervals (CI) for these associations. Cases with the XRCC1 codon 399 Gln/Gln genotype were positively associated with the presence of p53 transversions (OR = 4.8; 94% CI = 0.8-30). Cases with the XPD codon 751 Gln/Gln genotype were positively associated with the presence of p53 transitions (OR = 2.8; 95% CI = 0.8-9.3), in particular G:C-A:T transitions (OR = 3.7; 95% CI = 1.1-13). Our data provide some limited support for the hypothesis that mutations in the p53 gene in bladder cancer may differ according to the presence or absence of certain DNA repair gene variants.
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PMID:DNA repair gene polymorphisms and probability of p53 mutation in bladder cancer. 1665 73

Benzene is a recognized hematotoxicant and carcinogen that produces genotoxic damage. DNA double-strand breaks (DSB) are one of the most severe DNA lesions caused directly and indirectly by benzene metabolites. DSB may lead to chromosome aberrations, apoptosis and hematopoietic progenitor cell suppression. We hypothesized that genetic polymorphisms in genes involved in DNA DSB repair may modify benzene-induced hematotoxicity. We analyzed one or more single nucleotide polymorphisms (SNPs) in each of seven candidate genes (WRN, TP53, NBS1, BRCA1, BRCA2, XRCC3 and XRCC4) in a study of 250 workers exposed to benzene and 140 controls in China. Four SNPs in WRN (Ex4 -16 G > A, Ex6 +9 C > T, Ex20 -88 G > T and Ex26 -12 T > G), one SNP in TP53 (Ex4 +119 C > G) and one SNP in BRCA2 (Ex11 +1487 A > G) were associated with a statistically significant decrease in total white blood cell (WBC) counts among exposed workers. The SNPs in WRN and TP53 remained significant after accounting for multiple comparisons. One or more SNPs in WRN had broad effects on WBC subtypes, with significantly decreased granulocyte, total lymphocyte, CD4(+)-T cell, CD8(+)-T cell and monocyte counts. Haplotypes of WRN were associated with decreased WBC counts among benzene-exposed subjects. Likewise, subjects with TP53 Ex4 +119 C > G variant had reduced granulocyte, CD4(+)-T cell and B cell counts. The effect of BRCA2 Ex11 +1487 A > G polymorphism was limited to granulocytes. These results suggest that genetic polymorphisms in WRN, TP53 and BRCA2 that maintain genomic stability impact benzene-induced hematotoxicity.
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PMID:Polymorphisms in genes involved in DNA double-strand break repair pathway and susceptibility to benzene-induced hematotoxicity. 1672 35


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