Biomedical subjects

T Soussi

Publications and source records attributed to T Soussi.

At least 37 records · Page 2Linked to original sources

PubMed2001

[Genetics and cancer: fundamental and clinical aspects].

The twentieth century has witnessed the discovery of the various genetic alterations that drive a normal cell toward neoplasia. One the challenge of the near future concerns the diagnostic of these alterations and their correlation with clinical parameters such as response to therapy or survival. It will be important to define, for each patient, a specific profile of the various alterations in order to improve and personalize the therapy. It is also essential to understand the various mechanisms of these alterations in order to develop new diagnostic procedures. Furthermore, the relation between genotype and phenotype is not straightforward and can be influence by various parameters such as the localization of the mutation, alterations of other genes or the expression of modifiers genes.

Apoptosis↗

PubMed2000

Critical residues of epitopes recognized by several anti-p53 monoclonal antibodies correspond to key residues of p53 involved in interactions with the mdm2 protein.

The aim of this work was to study the reactivity of antibodies directed against the N-terminus of p53 protein. First, we analysed the cross-reactivity of anti-p53 antibodies from human, mouse and rabbit sera with peptides derived from human, mouse and Xenopus p53. Next, we characterized more precisely a series of monoclonal antibodies directed against the N-terminal part of p53 and produced by immunizing mice with either full length human or Xenopus p53. For each of these mAbs we localized the epitope recognized on human p53 by the Spot method of multiple peptide synthesis, defined critical residues on p53 involved in the interaction by alanine scanning replacement experiments and determined kinetic parameters using real-time interaction analysis. These antibodies could be divided into two groups according to their epitopic and kinetic characteristics and their cross-reactivity with murine p53. Our results indicate that critical residues involved in the interaction of some of these mAbs with p53 correspond to key residues on p53 involved in its interaction with the mdm2 protein. These antibodies could, therefore, represent powerful tools for the study of p53 regulation.

Alanine↗

PubMed2000

p53 Antibodies in the sera of patients with various types of cancer: a review.

p53 antibodies (p53-Abs) were discovered 20 years ago during the course of tumor-associated antigens screening. The discovery of p53 mutation and accumulation of p53 in human tumors shed new light on the p53 humoral response. In the present review, we have compiled more than 130 papers published in this specific field since 1992. We demonstrate that p53-Abs are found predominantly in human cancer patients with a specificity of 96%. Such antibodies are predominantly associated with p53 gene missense mutations and p53 accumulation in the tumor, but the sensitivity of such detection is only 30%. It has been demonstrated that this immune response is due to a self-immunization process linked to the strong immunogenicity of the p53 protein. The clinical value of these antibodies remains subject to debate, but consistent results have been observed in breast, colon, oral, and gastric cancers, in which they have been associated with high-grade tumors and poor survival. The finding of p53-Abs in the sera of individuals who are at high risk of cancer, such as exposed workers or heavy smokers, indicates that they have promising potential in the early detection of cancer.

Autoantibodies↗

PubMed2000

Prognostic significance of serum p53 antibodies in patients with limited-stage small cell lung cancer.

p53 tumour suppressor gene alterations are one of the most frequent genetic events in lung cancer. A subset of patients with p53 mutation and cancer exhibited circulating serum anti-p53 self-antibodies (p53-Ab). The prevalence of these antibodies in lung cancer is currently being analysed in a multicentric study. In a group of homogeneous SCLC patients, p53-Ab were detected in 20/97 (20.6%) individuals. In this group of patients, Cox's multivariate analysis identified disease extent (p = 0.022), WHO initial performance status greater than 0 (p = 0.005), and the absence of a complete response after 6 months of treatment (p < 0.0001) as independent prognostic variables, with p53-Ab being of borderline significance (p = 0.051). In the subset of limited-stage SCLC patients, Cox's multivariate analysis found p53-Ab (p = 0.033), WHO initial performance status greater than 0 (p = 0.028), and absence of a complete response (p < 0.001) to be independent prognostic variables. Thus, actuarial analysis showed that patients with limited-stage SCLC and p53-Ab had a median survival time of 10 months, whereas limited-stage SCLC patients without p53-Ab had a 17-month median survival time (p = 0.014).Therefore, serum assay of p53-Ab could help to identify a population of SCLC patients with an especially poor prognosis. This population could represent patients with tumours harboring aggressive p53 mutations.

Biomarkers↗

PubMed2000

p53 website and analysis of p53 gene mutations in human cancer: forging a link between epidemiology and carcinogenesis.

The p53 tumor suppressor gene has proven to be one of the genes most often mutated in human cancers. It involves mainly point mutations leading to amino acid substitutions in the central region of the protein which impairs normal functions. Analysis of the mutational events that target the p53 gene has revealed evidence for both exogenous and endogenous mutational mechanisms. For example, the p53 mutational spectrum reveals evidence for a direct causal effect of ultraviolet radiation in skin cancer, of aflatoxin B1 in liver cancer, and of tobacco smoke in lung cancer. This novel field, molecular epidemiology of human cancer risk, has added a new dimension to classical associative epidemiology by providing a direct link between human cancer and carcinogen exposure. For such analysis, we devised a generic software called UMD (Universal Mutation Database). It was developed as a generic software to create locus-specific databases (LSDBs) with the 4(th) Dimension(R) package from ACI. This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data.

Carcinogens↗

PubMed2000

UMD (Universal mutation database): a generic software to build and analyze locus-specific databases.

The human genome is thought to contain about 80,000 genes and presently only 3,000 are known to be implicated in genetic diseases. In the near future, the entire sequence of the human genome will be available and the development of new methods for point mutation detection will lead to a huge increase in the identification of genes and their mutations associated with genetic diseases as well as cancers, which is growing in frequency in industrial states. The collection of these mutations will be critical for researchers and clinicians to establish genotype/phenotype correlations. Other fields such as molecular epidemiology will also be developed using these new data. Consequently, the future lies not in simple repositories of locus-specific mutations but in dynamic databases linked to various computerized tools for their analysis and that can be directly queried on-line. To meet this goal, we devised a generic software called UMD (Universal Mutation Database). It was developed as a generic software to create locus-specific databases (LSDBs) with the 4(th) Dimension(R) package from ACI. This software includes an optimized structure to assist and secure data entry and to allow the input of various clinical data. Thanks to the flexible structure of the UMD software, it has been successfully adapted to nine genes either involved in cancer (APC, P53, RB1, MEN1, SUR1, VHL, and WT1) or in genetic diseases (FBN1 and LDLR). Four new LSDBs are under construction (VLCAD, MCAD, KIR6, and COL4A5). Finally, the data can be transferred to core databases.

Chromosome Mapping↗

PubMed2000

Expression of p53 in oral squamous cell carcinoma is associated with the presence of IgG and IgA p53 autoantibodies in sera and saliva of the patients.

Around 50% of head and neck cancers are known to have aberrations of the p53 gene. Overexpression of the mutant p53 protein can induce a specific humoral response in cancer patients. Matched saliva, serum, and tissue samples from 26 patients with histologically confirmed oral squamous and verrucous carcinoma were investigated. p53 protein expression was evaluated by immunohistochemistry and antibodies specific for 53 protein were analysed in sera and whole mouth saliva by ELISA, immunoprecipitation, and competition assays; 16/25 (64%) samples demonstrated the stabilized p53 protein in tissues and 7/26 (27%) had a high level of p53 antibody in serum. In samples where matching saliva was available, p53 antibody was also present in saliva. In some tumours, only IgA-type p53 antibody was detected. p53 antibodies were found only in the serum and saliva of patients who showed p53 overexpression in their tumour tissues. These results demonstrate that detection of p53 antibodies can offer a specific and non-invasive method for the detection of a subset of tumours with p53 aberrations.

Autoantibodies↗

PubMed2000

[Serum p53 antibody assay: evaluation in colorectal cancer].

INTRODUCTION: Alterations of the tumor suppressor gene p53 and its protein synthesis is the most commonly observed genetic feature in human cancers. Direct diagnosis of the gene mutation using sequencing is the gold standard method. However, it requires advanced technology and is only performed in specialized research units. CURRENT KNOWLEDGE AND KEY POINTS: Demonstration of intratumoral p53 protein accumulation using immunohistochemistry is a routine diagnostic technique. Serum detection of p53 antibodies using ELISA has been recently developed. It is an easily feasible and reproducible method for the diagnosis of p53 alterations due to self-immunization in some patients in response to intratumoral p53 protein overexpression. This phenomenon is inconstant (about one-third of the patients with a p53 gene mutation produce antibodies) and its mechanism is unclear. p53 Antibodies are found in 25% of the patients with colorectal cancer, independently of traditional tumor markers (carcinoembryonic antigen and carbohydrate antigen 19.9). The presence of these antibodies is not linked to the tumor stage. Since their ratios vary during the treatment, they might constitute a new tumor marker. FUTURE PROSPECTS AND PROJECTS: Early appearance of p53 serum antibodies during tumor development should make them useful for the detection of malignant transformation in patients with preneoplastic disease such as ulcerous colititis. Whether the presence of p53 antibodies in colorectal cancer patients has a prognostic significance requires further assessment.

Autoantibodies↗

PubMed2000

Serum p53 antibodies: predictors of survival in small-cell lung cancer?

Serum p53 antibodies have been shown to be a poor prognostic marker in resected non-small-cell lung cancer (NSCLC), but studies in small-cell lung cancer (SCLC) have been contradictory. We have studied the incidence of p53 antibodies in a large SCLC cohort treated at one oncology centre and correlated the results with survival. 231 patients (63% male, median age 65), diagnosed and treated for SCLC between 1987 and 1994 at The Royal Marsden Hospital NHS Trust, had sera stored pretreatment. All samples were tested for p53 antibodies (p53-Ab) using a standardized ELISA technique with a selection of strongly ELISA positive, weakly ELISA positive and negative samples being confirmed with immunoprecipitation. 54 patients were positive for p53-Ab (23%). The presence of a high titre of p53-Ab (titre ratio >5) appears to be associated with a survival advantage with a relative risk of death of 1.71 (95% CI: 1.14-2.58) in those without the antibody (P = 0.02). This study, the largest homogeneous group so far looking at p53-Ab in SCLC, suggests that p53 antibody detection may have a role in predicting outcome in this type of cancer.

Adult↗

PubMed2000

The p53 tumor suppressor gene: from molecular biology to clinical investigation.

The tumor suppressor p53 is a phosphoprotein barely detectable in the nucleus of normal cells. Upon cellular stress, particularly that induced by DNA damage, p53 can arrest cell cycle progression, thus allowing the DNA to be repaired; or it can lead to apoptosis. These functions are achieved, in part, by the transactivational properties of p53, which activate a series of genes involved in cell cycle regulation. In cancer cells bearing a mutant p53, this protein is no longer able to control cell proliferation, resulting in inefficient DNA repair and the emergence of genetically unstable cells. The most common changes of p53 in human cancers are point missense mutations within the coding sequences of the gene. Such mutations are found in all major histogenetic groups, including cancers of the colon (60%), stomach (60%), breast (20%), lung (70%), brain (40%), and esophagus (60%). It is estimated that p53 mutations are the most frequent genetic event in human cancers, accounting for more than 50% of cases. One of the most striking features of the inactive mutant p53 protein is its increased stability (half-life of several hours, compared to 20 min for wild-type p53) and its accumulation in the nucleus of neoplastic cells. Therefore, positive immunostaining is indicative of abnormalities of the p53 gene and its product. Several studies have shown that p53 mutations are associated with short survival in colorectal cancer, but the use of p53 as a tumoral marker is still a matter of debate.

Apoptosis↗

PubMed2000

p53 alterations predict tumor response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma: a prospective series.

PURPOSE: The tumor suppressor gene p53 plays a crucial role in cell cycle control and apoptosis in response to DNA damages. p53 gene mutations and allelic losses at 17p are one of the most common genetic alterations in primary head and neck squamous cell carcinoma (HNSCC). Alterations of the p53 gene have been shown to contribute to carcinogenesis and drug resistance. PATIENTS AND METHODS: In this prospective series, patients with HNSCC were treated with cisplatin-fluorouracil neoadjuvant chemotherapy. p53 status was characterized in 106 patients with HNSCC (p53 mutations, allelic losses at p53 locus, and plasma anti-p53 antibodies) to determine the existence of a relationship between p53 gene status and response to neoadjuvant chemotherapy. RESULTS: Exons 4 to 9 of the p53 gene were analyzed, and mutations were found in 72 of 106 patients with HNSCC. p53 mutations were associated with loss of heterozygosity at chromosome 17p (P <.001). The prevalence of p53-mutated tumors was higher in the group of patients with nonresponse to neoadjuvant chemotherapy than in the group of responders (81% v 61%, respectively; P <.04). When compiling p53 mutations and anti-p53 antibodies in plasma, the correlation between p53 status and response to chemotherapy was significant (87% v 57%, respectively; P =.003). A multivariate analysis showed that p53 status is an independent predictive factor of response to chemotherapy. CONCLUSION: This prospective study suggests that p53 status may be a useful indicator of response to neoadjuvant chemotherapy in HNSCC.

Adult↗

PubMed2000