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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fifty single-nucleotide polymorphisms (SNPs) associated with amino acid changes in 36 genes involved in diverse DNA repair pathways were assessed for associations with risk for small cell lung carcinoma (SCLC) by a case-control study consisting of 211 SCLC cases and 685 controls. An SNP, Val83Met, in the MTH1 (microtT homolog 1) gene encoding a triphosphatase that hydrolyzes pro-mutagenic oxidized nucleoside triphosphates, such as 8-hydroxy-dGTP and 2-hydroxy-dATP, showed the strongest and a significant association with SCLC risk [odds ratio (OR)=1.6, 95% confidence interval (CI): 1.2-2.2, P=0.004], while three other SNPs in the TP53, BLM and SNM1 genes, respectively, also showed marginal associations (0.05<P<0.1). Another SNP, which causes a nucleotide change in the 5'-UTR of MTH1 transcripts leading to alternative translation initiation, was additionally examined and the SNP also showed a significant association (OR=1.7, 95% CI: 1.2-2.3, P=0.002). The two SNPs in the MTH1 gene were in linkage disequilibrium, and the OR for carrying a copy of the haplotype consisting of both the risky SNP alleles was 2.0 (95% CI: 1.2-3.2, P=0.002). The present results indicate that inter-individual differences in MTH1 activities due to SNPs are involved in susceptibility to SCLC.
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PMID:Association of polymorphisms in the MTH1 gene with small cell lung carcinoma risk. 1677 34

Bloom's syndrome is a genetic disorder characterized by increased incidence of cancer and an immunodeficiency of unknown origin. The BLM gene mutated in Bloom's syndrome encodes a DNA helicase involved in the maintenance of genomic integrity. To explore the role of BLM in the immune system, we ablated murine Blm in the T-cell lineage. In the absence of Blm, thymocytes were severely reduced in numbers and displayed a developmental block at the beta-selection checkpoint that was partially p53 dependent. Blm-deficient thymocytes rearranged their T-cell receptor (TCR) beta genes normally yet failed to survive and proliferate in response to pre-TCR signaling. Furthermore, peripheral T cells were reduced in numbers, manifested defective homeostatic and TCR-induced proliferation, and produced extensive chromosomal damage. Finally, CD4(+) and CD8(+) T-cell responses were impaired upon antigen challenge. Thus, by ensuring genomic stability, Blm serves a vital role for development, maintenance, and function of T lymphocytes, suggesting a basis for the immune deficiency in Bloom's syndrome.
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PMID:The Bloom's syndrome helicase is critical for development and function of the alphabeta T-cell lineage. 1721 Jun 42

Breast carcinomas are graded according to the "Nottingham modification of the Bloom-Richardson system" (SBR). The system is hindered, however, by lack of precision in assessing all three parameters including nuclear grade, mitosis, and tubular formation, leading to an element of subjectivity. Our objective was to evaluate a new grading system [the nuclear grade plus proliferation (N+P) system] for subjectivity, ease, and better representation of tumor biology. Its components are nuclear grade and automated proliferation index. Invasive ductal carcinomas, consisting of 137 SBR grade I, 247 grade II, and 266 grade III, were re-evaluated by the N+P system. The two systems were compared with each other and correlated with patients' overall survival, tumor size, angiolymphatic invasion, lymph node status, and biomarker status including estrogen receptor, progesterone receptor, p53, epidermal growth factor receptor, BCL-2, and Her-2. Although there was an agreement between the two systems with histologic and prognostic parameters studied, there was 37% disagreement when grading individual tumors. Fifty-three percent of SBR grade II tumors were "down-graded" to N+P grade I, and 7% were "up-graded" to N+P grade III. Distinction among the different histologic grades for overall survival curves was better indicated by the N+P than the SBR system.
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PMID:Grading invasive ductal carcinoma of the breast: advantages of using automated proliferation index instead of mitotic count. 1745 58

The Bloom syndrome helicase BLM and the tumor-suppressor protein p53 play important roles in preserving genome integrity. Here, we knock out the genes for BLM and p53 in a human pre-B-cell line, Nalm-6. We show that p53 plays an important role in cell proliferation, but not apoptosis, when BLM is absent. Intriguingly, despite the apoptotic function of p53, BLM(/)TP53(/) cells were more sensitive than either single mutant to etoposide, an anticancer agent that poisons DNA topoisomerase II. Our results suggest a direct, BLM-independent role for p53 in etoposide-induced, topoisomerase II-mediated DNA damage in human cells.
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PMID:Absence of p53 enhances growth defects and etoposide sensitivity of human cells lacking the Bloom syndrome helicase BLM. 1763 Aug 56

Available data involve neurotrophins and their receptors in carcinomas. Quantitative evaluation of these molecules in these tumors might be useful as prognostic marker and eventual treatments. Our study on 40 mammary tumors tries to correlate expression of these molecules and prognosis. Immunohistochemistry for NGF, BDNF, NT3, TrkA, TrkB, TrkC, and p75 was used. Patient's age, histopathology, Bloom-Richardson grading, estrogen and progesterone receptors, Ki-67 index, HER-2, p53 were evaluated. Statistics found inverse relationship between grading and TrkC expression. We found significantly higher TrkC expression in Grade I than in Grade III tumors. Rise in TrkC expression could indicate good prognosis.
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PMID:TrkC: a new predictive marker in breast cancer? 1788 51

Breast carcinoma is the most common malignant tumour and the main cause of carcinoma death in women. There has been a sharp increase in the detection of breast carcinoma, although mortality is still unvaried. In the last ten years the incidence of breast cancer measuring less than 1 cm, corresponding to pT1a, pT1b in TNM stadiation, has greatly increased. The present study describes the biologic characterisation of small breast carcinomas. The Nottingham/Tenovus Primary Breast Cancer Study stated that tumour size is a significant, independent factor for breast cancer prognosis. Cases were selected among formalin-fixed, paraffin-embedded tissues from 360 ductal breast cancers. In one-half of cases, the tumour was less than 1 cm in diameter, pT1a- pT1b; in the other half the tumour size was greater than 1 cm, but less than 2 cm, pT1c. Histological grading was assessed with the Scarff-Bloom-Richardson method, without Nottingham grade. Immunohistochemical determinations for ER, PgR, Ki-67, Her-2/Neu, CD34, p53, EGFR were done with an automated method. From the above analyses, it was demonstrated that the tumour size is indeed an important prognostic factor, particularly in cases without lymph node metastasis (N0). In particular, we observed significant differences between pT1a-b and pT1c cases, confirming that tumour size is an important criterion for prognostic valuation in ductal breast cancer without lymph node metastasis.
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PMID:[Breast cancer less than 1 cm: bio-morphologic characterization with ER, PgR, Ki67, Her-2/Neu, MDV, MAGS, p53, EGF-R]. 1884 18

Benzene is an established human hematotoxicant and leukemogen but its mechanism of action is unclear. To investigate the role of single-nucleotide polymorphisms (SNPs) on benzene-induced hematotoxicity, we analyzed 1395 SNPs in 411 genes using an Illumina GoldenGate assay in 250 benzene-exposed workers and 140 unexposed controls. Highly significant findings clustered in five genes (BLM, TP53, RAD51, WDR79 and WRN) that play a critical role in DNA repair and genomic maintenance, and these regions were then further investigated with tagSNPs. One or more SNPs in each gene were associated with highly significant 10-20% reductions (P values ranged from 0.0011 to 0.0002) in the white blood cell (WBC) count among benzene-exposed workers but not controls, with evidence for gene-environment interactions for SNPs in BLM, WRN and RAD51. Further, among workers exposed to benzene, the genotype-associated risk of having a WBC count <4000 cells/microl increased when using individuals with progressively higher WBC counts as the comparison group, with some odds ratios >8-fold. In vitro functional studies revealed that deletion of SGS1 in yeast, equivalent to lacking BLM and WRN function in humans, caused reduced cellular growth in the presence of the toxic benzene metabolite hydroquinone, and knockdown of WRN using specific short hairpin RNA increased susceptibility of human TK6 cells to hydroquinone toxicity. Our findings suggest that SNPs involved in DNA repair and genomic maintenance, with particular clustering in the homologous DNA recombination pathway, play an important role in benzene-induced hematotoxicity.
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PMID:Large-scale evaluation of candidate genes identifies associations between DNA repair and genomic maintenance and development of benzene hematotoxicity. 1897 39

The RecQ family helicase BLM is critically involved in the maintenance of genomic stability, and BLM mutation causes the heritable disorder Bloom's syndrome. Affected individuals suffer from a predisposition to a multitude of cancer types and an ill-defined immunodeficiency involving low serum Ab titers. To investigate its role in B cell biology, we inactivated murine Blm specifically in B lymphocytes in vivo. Numbers of developing B lymphoid cells in the bone marrow and mature B cells in the periphery were drastically reduced upon Blm inactivation. Of the major peripheral B cell subsets, B1a cells were most prominently affected. In the sera of Blm-deficient naive mice, concentrations of all Ig isotypes were low, particularly IgG3. Specific IgG Ab responses upon immunization were poor and mutant B cells exhibited a generally reduced Ab class switch capacity in vitro. We did not find evidence for a crucial role of Blm in the mechanism of class switch recombination. However, a modest shift toward microhomology-mediated switch junction formation was observed in Blm-deficient B cells. Finally, a cohort of p53-deficient, conditional Blm knockout mice revealed an increased propensity for B cell lymphoma development. Impaired cell cycle progression and survival as well as high rates of chromosomal structural abnormalities in mutant B cell blasts were identified as the basis for the observed effects. Collectively, our data highlight the importance of BLM-dependent genome surveillance for B cell immunity by ensuring proper development and function of the various B cell subsets while counteracting lymphomagenesis.
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PMID:Genomic instability resulting from Blm deficiency compromises development, maintenance, and function of the B cell lineage. 1910 66

Invasive ductal carcinoma (IDC) of the breast is currently graded according to the Nottingham modification of the Scarff-Bloom-Richardson system (SBR). This system involves subjective evaluation of 3 morphologic features: tubule formation, nuclear pleomorphism, and mitosis. Our recently proposed semi-automated Nuclear and Proliferation Index [N+P] grading system for IDC has demonstrated agreement among grades and prognostic markers with better prediction of patient survival than the SBR system. Our present objective is to expand the utilization of the N+P system to grading invasive lobular carcinoma (ILC). Fifty-eight ILC cases were evaluated by the SBR and N+P systems. The 2 systems were compared in terms of correlation with patient survival, tumor size, grade, angiolymphatic invasion, lymph node status, ploidy status, and ER, PR, Her-2, p53, EGFR, and Bcl-2 staining. The N+P and SBR systems demonstrated overall agreement when correlated with clinical and prognostic parameters. Twenty-four of 30 tumors initially classified as SBR Grade II were down-graded to N+P I. Three of 26 tumors initially classified as SBR Grade I were up-graded to N+P II. Grading of ILC provides valuable predictive and prognostic information. The N+P grading system for ILC decreases the element of subjectivity for assessing mitotic activity and appears to be superior to the SBR system in predicting patient survival.
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PMID:A newly proposed semi-automated method of grading invasive lobular carcinoma: a unifying concept and correlation with prognostic markers and patient survival. 1920 37

Acute myeloid leukemia in childhood is a heterogeneous group of diseases, and different epidemiologic factors are involved in the etiopathogenesis. Genetic syndromes are one of the predisposing factors of acute myeloid leukemia (AML), including Down syndrome, Bloom syndrome, and neurofibromatosis. Acute megakaryoblastic leukemia (AMKL) is the main subtype in Down syndrome infants, and acquired chromosomal anomalies are closely related to the physiopathology of the illness. The main chromosomal anomalies in AMKL are structural, such as t(1;22); however, complex karyotypes are also common. Here we describe the case of an infant with neurofibromatosis developing AMKL with a complex karyotype including 5q and 17q deletions, TP53 deletion, and an unusual unbalanced chromosomal translocation t(11;19)(q13;p13), leading to three copies of the MLL gene.
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PMID:Complex karyotype defined by molecular cytogenetic FISH and M-FISH in an infant with acute megakaryoblastic leukemia and neurofibromatosis. 2062 Jun 1


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