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T Soussi

Publications and source records attributed to T Soussi.

At least 73 records · Page 4Linked to original sources
PubMed1998

Databases and software for the analysis of mutations in the human p53 gene, human hprt gene and both the lacI and lacZ gene in transgenic rodents.

We have created databases and software applications for the analysis of DNA mutations at the human p53 gene, the human hprt gene and both the rodent transgenic lacI and lacZ loci. The databases themselves are stand-alone dBASE files and the software for analysis of the databases runs on IBM-compatible computers with Microsoft Windows. Each database has a separate software analysis program. The software created for these databases permit the filtering, ordering, report generation and display of information in the database. In addition, a significant number of routines have been developed for the analysis of single base substitutions. One method of obtaining the databases and software is via the World Wide Web. Open the following home page with a Web Browser: http://sunsite.unc.edu/dnam/mainpage. html . Alternatively, the databases and programs are available via public FTP from: anonymous@sunsite.unc.edu. There is no password required to enter the system. The databases and software are found beneath the subdirectory: pub/academic/biology/dna-mutations. Two other programs are available at the site, a program for comparison of mutational spectra and a program for entry of mutational data into a relational database.

Animals↗
PubMed1998

p53 gene mutation: software and database.

A large number of different mutations in the p53 tumor suppressor gene have been identified in all types of cancer. As of October, 1997, this database (http:// perso.curie.fr/tsoussi ) contained >7500 mutations. Such a substantial increase since our previous reports should enable epidemiological analyses which were not previously possible. In order to analyse these new data, the UMD software has been improved. A new Web version of the UMD software enables online analysis of the database. The present report describes various improvements since the last release of the database.

Animals↗
PubMed1998

APC gene: database of germline and somatic mutations in human tumors and cell lines.

A database (http://perso.curie.fr/tsoussi ) is described, in which over 1000 mutations in the human APC gene of tumors (colon cancer predominantly) are compiled from the literature. It includes both molecular information about the mutations and clinical data about the patients. Software has been designed to analyse all this information in the database.

Adenomatous Polyposis Coli↗
PubMed1998

Is p53 a protein that predicts the response to chemotherapy in node negative breast cancer?

The role of p53 in modulating apoptosis has suggested that it may affect efficacy of anti cancer agents. For this reason, we have evaluated p53 alterations in 282 consecutive patients with infiltrating node-negative breast cancer who underwent primary surgery and were randomized either to CMF (Cyclophosphamide 400 mg/m2, Fluorouracil 400 mg/m2, and Methotrexate 40 mg/m2) or control arm (no adjuvant therapy) from 1980 to 1989. p53 alterations were analyzed by immunohistochemistry using DO7 MoAb, revealed by immunoperoxidase technique, and quantitated in term of percentage of positive cells. We observed a positive staining in 24% of the tumors. Among them, 10% had a positive staining in more than 75% of the cells. There was a highly significant association between the proportion of positive cells and histologic grade of the infiltrating ductal carcinomas (p<0.004). However, there was no association with age, tumor size, hormone receptor content, or vascular embolism. There was a trend but no significant relationship between positive staining and overall survival either in each arm of the trial or in the overall population. Interestingly, we observed a higher relative risk of local relapse after conservative therapy in the boosted area in the group of mutated p53 (RR=4.41; p<0.0005). We conclude that, in this node-negative breast tumor population, alteration of p53 cannot predict the response to the chemotherapy. However, it may represent a useful marker of risk of local relapse and of radio resistance.

Adult↗
PubMed1998

Very low incidence of p53 antibodies in adult non-Hodgkin's lymphoma and multiple myeloma.

In several types of solid tumours, circulating antibodies to p53 are seen in about a third of cases with a p53 mutation, but are absent in cases without p53 mutation. Therefore detection of those antibodies has relatively low sensitivity but high specificity in the detection of p53 mutations. We looked for circulating p53 antibodies by ELISA in 56 adult non-Hodgkin's lymphoma (NHL) and 80 multiple myeloma cases. A certain or highly probable p53 mutation was found by SSCP analysis, immunocyto- or immunohistochemistry in 8/35 (23%) NHL cases and 2/19 (10%) MM cases analysed by these techniques. None of the 80 MM cases and only one of the 56 cases of NHL had circulating p53 antibodies. The positive case had Burkitt's lymphoma and a p53 missense mutation at codon 273. Thus, very few MM and NHL patients with a p53 mutation develop p53 antibodies and this test does not appear to be useful in haematological malignancies.

Antibodies↗
PubMed1998

Monitoring of p53 autoantibodies in lung cancer during therapy: relationship to response to treatment.

Alteration of the p53 gene is the most frequent genetic alteration in human cancer, and it leads to the accumulation of mutant p53 in the nucleus of tumor cells. In addition, it has been shown that patients with various types of neoplasias have p53 antibodies in their sera. ELISA was used to detect anti-p53 antibodies in their sera of 167 patients with lung cancer. Among these, 32 individuals (16 positive for p53 antibodies and 16 negative) were monitored over a period of 30 months for p53 antibodies. Twelve of 16 antibody positive patients had reduced titers during chemotherapy that led to partial or complete remissions of disease. The specificity of these antibodies was confirmed by two different ELISA procedures and by immunoprecipitation. The very rapid, specific decrease in these antibodies during therapy suggests that a constant level of tumoral cells with nuclear accumulating p53 protein is necessary for a detectable humoral anti-p53 response. The good correlation found between the specific evolution of the p53 antibody titer and the response to therapy suggests that p53 antibodies could represent a useful tool for checking the response to therapy and for monitoring some relapses before they are clinically detectable.

Antibody Formation↗
PubMed1997

Lymphomas in patients with Sjogren's syndrome are marginal zone B-cell neoplasms, arise in diverse extranodal and nodal sites, and are not associated with viruses.

The occurrence of non-Hodgkin's lymphoma (NHL) is the most serious complication of Sjogren's syndrome (SS). We performed a study of 16 NHLs occurring in patients with an underlying SS. These lymphomas arose not only in salivary glands (7 cases) but also in other mucosal extranodal sites (the stomach [4 cases], the lung [3 cases], the skin [3 cases], the buccal mucosa [1 case], the thymus [1 case]) and in nodal sites (8 cases). Low-grade marginal zone lymphomas (MZL) were diagnosed in 12 of the 16 patients, 9 of mucosa-associated lymphoid tissues (MALT) type in mucosal sites and 3 exclusively nodal. The 4 other patients presented with a high-grade B-cell lymphoma that was probably a histological transformation of an underlying low-grade MZL at least in 3 of the cases involving skin, stomach, and parotid, respectively. A t(14;18) translocation was detected in 1 of 8 lymphomas tested. We detected serum anti-p53 antibodies in 2 of the 14 studied patients. p53 protein was detected in 1 of 11 lymphomas tested. LMP protein and Eber RNAs of Epstein-Barr virus (EBV) were not detected in the 16 NHL biopsies. Using polymerase chain reaction, EBV was never detected except in 1 of 4 parotid lymphomas. No human T-lymphotropic virus 1 or human herpes virus 8 DNAs were detected in NHL biopsies. None of the patients had hepatitis C virus infection found using serological methods. Chemotherapy was usually efficient. In conclusion, lymphomas occurring in patients with an underlying SS are in most cases MZL. These lymphomas are not associated with viruses known to be present in other types of lymphomas. Some of the translocations or mutations of oncogenes or antioncogenes described in other lymphomas are detected in SS-associated lymphomas.

Adolescent↗
PubMed1997

Increase of spontaneous intrachromosomal homologous recombination in mammalian cells expressing a mutant p53 protein.

Homologous recombination plays an essential role in processes involved in genome stability/instability, such as molecular evolution, gene diversification, meiotic chromosome segregation, DNA repair and chromosomal rearrangements. p53 devoid cells exhibit predisposition to neoplasia, defects in G1 checkpoint and high genetic instability but a normal rate of point mutations. We investigated the effect of a p53 mutation, on spontaneous homologous recombination between intrachromosomal direct repeat sequences, in mouse L cells. In these cells, wild type for the p53 gene, we have overexpressed the mutant p53(175(Arg>His)) protein leading to a p53 mutant phenotype, as verified by the absence of a G1 arrest after gamma-irradiation. We show that the rate of spontaneous recombination is increased from five- to 20-fold in the mutant p53 lines. Moreover, this increase is observed in gene conversion as well as in deletion events. Our results provide new insights into the molecular mechanisms of genetic instability due to a defect of p53.

Animals↗
PubMed1997

Databases and software for the analysis of mutations in the human p53 gene, the human hprt gene and both the lacI and lacZ gene in transgenic rodents.

We have created databases and software applications for the analysis of DNA mutations at the humanp53gene, the humanhprtgene and both the rodent transgeniclacIandlacZlocus. The databases themselves are stand-alone dBASE files and the software for analysis of the databases runs on IBM-compatible computers. Each database has a separate software analysis program. The software created for these databases permit the filtering, ordering, report generation and display of information in the database. In addition, a significant number of routines have been developed for the analysis of single base substitutions. One method of obtaining the databases and software is via the World Wide Web (WWW). Open the following home page with a Web Browser: http://sunsite.unc.edu/dnam/mainpage.ht ml . Alternatively, the databases and programs are available via public FTP from: anonymous@sunsite.unc.edu . There is no password required to enter the system. The databases and software are found beneath the subdirectory: pub/academic/biology/dna-mutations. Two other programs are available at the site-a program for comparison of mutational spectra and a program for entry of mutational data into a relational database.

Animals↗
PubMed1997

p53 and APC gene mutations: software and databases.

A large number of different mutations in the APC and p53 tumor suppressor genes have been identified in various types of cancer. This substantial increase since our previous reports can enable analyses which were not previously possible. In order to capture all these new data, the software permitting analysis has been improved. This report describes the various improvements since the second release of the database.

Databases, Factual↗
PubMed1997

Database of p53 gene somatic mutations in human tumors and cell lines: updated compilation and future prospects.

In recent years, there has been an exponential increase in the number of p53 mutations identified in human cancers. The p53 mutation database consists of a list of point mutations in thep53 gene of human tumors and cell lines, compiled from the published literature and made available through electronic media. The database is now maintained at the International Agency for Research on Cancer (IARC) and is updated twice a year. The current version contains records on 5091 published mutations and is expected to surpass the 6000 mark in the January 1997 release. The database is available in various formats through the European Bioinformatics Institute (EBI) ftp server at: ftp://ftp.ebi.ac.uk/pub/databases/p53/ or by request from IARC (p53database@iarc.fr) and will be searchable through the SRS system in the near future. This report provides a description of the criteria for inclusion of data and of the current formats, a summary of the relevance ofp53 mutation analysis to clinical and biological questions, and a brief discussion of the prospects for future developments.

Databases, Factual↗
PubMed1997

A functional analysis of p53 during early development of Xenopus laevis.

p53 is a nuclear protein that acts like a tumor suppressor and is involved in regulation of cellular growth. In Xenopus, the p53 protein is highly expressed during oogenesis and is strictly cytoplasmic in the oocyte. We have analysed its participation in DNA replication and transcription during early development, using the egg and oocyte as model-systems. The injection of sperm nuclei into Xenopus eggs is followed by DNA replication and mitotic events. We show that the endogenous p53 enters the nuclei and moves through a series of discrete sub-nuclear loci whose distribution is S-phase specific. A specific peripheral nuclear localization of p53 is observed before entry into S-phase, followed by an internal localization which is strictly dependent on ongoing DNA synthesis. At no stage in the cell cycle, however, did we observe any co-localization with RPA or PCNA, which were used as initiation or elongation markers for DNA replication. We also show that injection into the nucleus of the oocyte of small amounts of either Xenopus or human p53 - less than 10% of the cytoplasmic storage - is sufficient to block RNA polymerase II-dependent transcription from a coinjected TATA-box-containing reporter plasmid. Transcription is rescued by microinjection of the TATA-box binding protein (TBP), suggesting that nuclear exclusion of p53 during oogenesis may be necessary for transcription of maternal genes. These characteristics are discussed in relation to the regulation of nuclear activities during early embryogenesis.

Animals↗
PubMed1997

Detection and monitoring of serum p53 antibodies in patients with colorectal cancer.

BACKGROUND: Detection of p53 antibodies in serum might be an effective indirect procedure to detect alterations of the p53 gene. AIMS: To assess the prevalence and the variation under treatment of p53 antibodies in patients with colorectal cancer. PATIENTS AND METHODS: Fifty four patients with colorectal cancer (26 men and 28 women, mean age 65, range 33-90 years) and 24 patients with non-malignant digestive disease were tested for p53 antibodies by enzyme linked immunosorbent assay (ELISA), and for the carcinoembryonic antigen and carbohydrate antigen 19.9. Immunohistochemical detection of p53 protein tumour overexpression was performed in 38 cases. RESULTS: Fourteen patients (26%) with colorectal cancer but none of those with non-malignant disease displayed p53 antibodies. Overexpression of p53 was shown by immunohistochemistry in 22 patients (58%), 10 of whom also had p53 antibodies. The antibodies were present in four patients with high carcinoembryonic antigen and three patients with high carbohydrate antigen 19.9 concentrations, but also in 10 patients (33.3%) with normal values of these markers. The ratio of p53 antibodies decreased in 11 of 13 patients after tumour resection. In two patients variations in p53 ratio strongly correlated with tumour relapse or progression. CONCLUSION: Testing for serum p53 antibodies constitutes a useful technique for assessing alterations in p53 and may help physicians to follow up patients with colorectal cancer.

Adenocarcinoma↗
PubMed1996

Regulation of mutant p53 temperature-sensitive DNA binding.

We have examined in detail the DNA binding properties of several immunopurified tumor-derived mutant p53 proteins (Val-143 --> Ala, Arg-175 --> His, Arg-248 --> Trp, Arg-249 --> Ser, and Arg-273 --> His). While all mutants were defective for binding to DNA at 37 ;C, each bound specifically to several cognate p53 binding sites at sub-physiological temperatures (25-33 ;C), and several mutants activated transcription from a p53-responsive promoter at 26 degrees C in transfected H1299 cells. Heating mutant p53 proteins at 37 degrees C irreversibly destroyed their ability to subsequently bind at 25 degrees C. However, several different monoclonal antibodies that each share the ability to recognize an epitope encompassing amino acids 46-55 markedly stabilized binding by mutant p53 proteins at 37 degrees C. Both intact antibody and FAb fragments allowed mutant p53 to bind to DNA. By contrast, antibodies that recognize epitopes located elsewhere within p53 stabilized mutant p53 binding significantly less effectively. Our data show that the major hot-spot p53 mutants have the intrinsic ability to bind to DNA and that a unique region within the N terminus of p53 may be critical for rescuing them from loss of binding at physiological temperatures. This suggests the possibility of developing small molecules that can stabilize mutant p53 proteins under physiological conditions.

Amino Acid Sequence↗
PubMed1996

Analysis of p53 serum antibodies in patients with head and neck squamous cell carcinoma.

BACKGROUND: Mutation of the p53 tumor suppressor gene (also known as TP53) often leads to the synthesis of p53 protein that has a longer than normal half-life. Mutant p53 protein that accumulates in tumor cell nuclei can be detected by means of immunohistochemical staining techniques. Serum antibodies directed against p53 protein (p53-Abs) have been detected in some cancer patients. PURPOSE: We assayed serum samples from 80 patients with head and neck squamous cell carcinoma (HNSCC) for the presence of p53-Abs, and we evaluated potential associations between the presence of these antibodies and other histopathologic and clinical features. METHODS: Serum was collected from each patient at the time of diagnosis. In addition, tumor biopsy specimens were obtained before the initiation of treatment. An enzyme-linked immunosorbent assay was used to detect p53-Abs. The accumulation of p53 protein in tumor cell nuclei was assessed immunohistochemically by use of the anti-p53 monoclonal antibody DO7. Patient treatment consisted of radiotherapy alone, primary chemotherapy followed by radiotherapy, or surgery and postoperative radiotherapy. Relapse-free and overall survival from the beginning of treatment were estimated by use of the Kaplan-Meier method; survival comparisons were made by use of the logrank statistic. Univariate and multivariate analyses were conducted to identify factors associated with survival. Reported P values are two-sided. RESULTS: Fifteen (18.8%) of the 80 patients had p53-Abs. Tumor cell nuclei in 43 (58.9%) of 73 assessable biopsy specimens exhibited strong p53 immunostaining. Patient treatment method and the accumulation of p53 protein in tumor cell nuclei were not associated with increased risks of relapse or death. In univariate analyses, advanced tumor stage (> T1 [TNM classification]) and the presence of p53-Abs were significantly associated with an increased risk of death (P for trend = .007 and P = .002, respectively), whereas advanced tumor stage, substantial regional lymph node involvement (> N1), and the presence of p53-Abs were associated with an increased risk of relapse (P for trend = .002, P = .02, and P < .0001, respectively). In multivariate analyses, advanced tumor stage and the presence of p53-Abs were significantly associated with increased risks of relapse (p for trend = .04 and P = .003, respectively) and death (P for trend = .04 and P = .03, respectively). At 2 years of follow-up, the overall survival proportion was 63% (95% confidence interval [CI] = 47%-80%) when no p53-Abs were detected compared with 29% (95% CI = 4%-54%) when p53-Abs were detected. Relapse-free survival at 2 years was 62% (95% CI = 49%-76%) if no p53-Abs were detected compared with 13% (95% CI = 0%-31%) if p53-Abs were detected. CONCLUSIONS AND IMPLICATIONS: The proportion of patients with HNSCC who have serum p53-Abs is smaller than that of patients exhibiting tumor cell accumulation of p53 protein. The presence of p53-Abs is significantly associated with increased risks of relapse and death.

Aged↗