The p53 protein is a transcription factor activated in response to DNA-damaging agents (such as chemical or physical carcinogens) and which plays multiple role in the control of proliferation and survival of cells exposed to genotoxic stress. Recent developments in the analysis of the crystal structure of p53 help us to understand the exact role of the various domains of the protein, as well as the impact of the mutations which are frequently found in cancers. In the future, this structural approach may significantly contribute to the interpretation of the pathological consequences of p53 mutations.

The "guardian of the genome" p53 is an essential modulator of the cellular response to cytotoxic agents. After introduction of DNA damages, the p53 protein prevents the cells to divide, either transiently by arresting their progression at the G1/S transition, or definitely by inducing apoptosis. In approximately half of the human tumors, mutations result in profound alterations of the p53 protein properties. In this work, the consequences of these alterations on the tumor cell sensitivity to chemotherapy are discussed.

The Li-Fraumeni syndrome is an autosomal dominant syndrome representing a genetic predisposition to a wide spectrum of tumours including sarcomas, breast carcinomas, brain tumors and adrenocortical carcinomas. In most of the cases, tumours will develop in children and young adults. Germline mutations of the tumor suppressor gene p53 have been identified in approximately 50% of the families. In most of the cases, germline p53 mutations are missense mutations, located between exon 5 and exon 8, within the DNA-binding domain of p53. Since these mutations inactivate the transcriptional activity of the protein, they can easily be detected by analyzing in yeast the transcriptional competence of p53 cDNA derived from lymphocytes. The presence of a germline p53 mutations must be considered in: (1) families including two first degree relatives with cancers belonging to the Li-Fraumeni spectrum, one relative being affected before age 45; (2) children or young adults with a rare tumour of in the general population, belonging to the Li-Fraumeni spectrum, such as adrenocortical carcinoma; and (3) children or young adults under age 45 with multiple primary tumours of the Li-Fraumeni spectrum. Identification of a germline p53 mutation in an affected subject allows to establish the diagnosis of the Li-Fraumeni syndrome on a molecular basis.

The possibility to perform flow cytometry was examined in a series of 167 patients with primary untreated head and neck carcinoma referred to our Institution from February 1989 to January 1992. In all cases, flow cytometry was carried out on frozen tumour samples. The Cox model was used including age, tumour size, nodal status on clinical assessment, topography, treatment, malignancy grade, S phase fraction and ploidy as independent variables and overall survival as dependent variable. In this study, ploidy could be assessed in only 73% of cases and S phase fraction and G2M in 65% of the population studied. No correlation could be evidenced between ploidy or SPF with other clinical, pathologic characteristics or clinical outcome. We conclude that flow cytometry should remain a research tool until the method has proved to be relevant in clinical routine, and until the yield of the technique can be improved.

Much of our understanding of the molecular anomalies involved in the process of oncogenesis has resulted from research into malignant hematologic diseases, facilitated by the accessibility of hematopoietic cells. For example, in lymphoid tumors, rearrangement of the genomic DNA can lead to the juxtaposition of proto-oncogenes and the highly active sequences regulating synthesis of immunoglobulins or T-cell receptors. The subsequent malignancy results from an uncontrolled overexpression of a normal protein. This type of "quantitative" anomaly occurs in follicular lymphomas where B-cells overexpress the normal BCL2 protein which inhibits apoptosis, contributing to immortalization of the B done. The same type of rearrangement process can approach gene fragments which fusion and lead to production of a highly oncogenic chimerical or truncated abnormal protein. Such "qualitative" anomalies occur in myeloid hemopathies. Both types of anomalies involve genes controlling the cell cycle, cell differentiation or cell death (apoptosis), in particular transcription factors (for example, E2A, RARA, MYC) and molecules involved in signal transduction (for example RAS, ABL, LCK). A molecular anomaly can be detected in approximately 30% of all cases of acute leukemia and in up to 75% of the non-Hodgkin lymphomas. Analysis of the junction fragments of the different heavy chains of the immunoglobulins produced in these cases provides a specific marker for detecting the B or T-cell clone in digestive or skin biopsies. For example, detection of a BCR-ABL transcript in a patient with primary thrombocythemia or an atypical myeloproliferative syndrome can be diagnostic and detection of the donal immunoglobulin or T-cell receptor rearrangement can confirm the malignant nature of the lymphoid proliferation. Molecular markers also have prognostic value allowing patient stratification and more adapted therapy. Molecular anomalies detected in malignant hematologic diseases are thus examples of nearly perfect "tumor-specific" markers.

Prognostic factors have been so far much more extensively studied for resectable colorectal cancers than for advanced colorectal cancers. However, the recent increase in treatment possibilities forces physicians to take into account the prognostic factors of patients with advanced colorectal cancer. The prognostic evaluation of these patients is still mostly based on clinical parameters, such as performance status and allocated treatment. More recently, the prognostic role of biological parameters such as p53 gene or enzymes implicated in 5-fluorouracil metabolisms has been identified.

Pharmacogenetics could be defined as the study of genetically controlled variations in drug response. Introduction of pharmacogenetics in hematology and oncology has been done recently. With recombinant DNA technology, like restriction analysis of genomic DNA, enzymatic amplification of DNA by the polymerase chain reaction and expression of cDNAs in cell cultures, this research area has been developed during the last 10 years. In hematology and oncology, we can integrate pharmacogenetics in 3 areas. First, the concept of genetic risk of cancer and the study of drug or carcinogen metabolizing enzymes that could modulate this risk, regarding the activity of some specific enzymes; second, the use of pharmacogenetics, related to the toxicity or efficacy of anticancer drugs, allowing the identification of key enzymes involved in the biotransformation of the drug and the study of molecular aspects involved in the regulation of the activity of the enzymes; third, the implication of the study of enzymatic activities in tumoral tissues as compared to non-tumoral tissues. The following differences between the 2 tissues can be subsequently used to increase the specificity of the anticancer drugs.

We report here a rare differentiation of an embryonal carcinoma of the testis to a peripheral neurectodermal tumor (PNET) with lymph nodes and lung metastases. In the present case a complete remission was obtained by a PNET oriented chemotherapy combination followed by 2 courses of classical BEP.

To assess the prognostic value of flow cytometric analysis, 61 cases of operated squamous cell lung carcinoma were studied in terms of desoxyribonucleic acid (DNA) nuclear content and percentage of cells in DNA synthesis phase (% S). These parameters were determined on a fresh surgical sample. The S % was obtained in 25 cases. DNA index (DI) and % S were compared with survival and usual clinicopathologic characteristics for the prediction of survival. DNA content classified as DNA-diploid and DNA-aneuploid is not a prognostic factor for survival. DI higher than 2 seems to be predictive but needs confirmation. The % S and multiploidy are not predictive factors for survival.

The possibility of maintaining and studying human prostatic cancers in an in vitro and in vivo environment has allowed the development of rare but essential tools to study many aspects of the biology of these cancers. Although none of the available models is perfect, the sum of the studies conducted with these models over more than 20 years constitutes the basis for major progress in our understanding of this disease. The most widely used cell lines (cultured in vitro) are PC-3, DU-145 and LNCaP. They are limited by the fact that they are essentially androgen-independent cell lines, derived from metastatic sites. Due to the slow growth of prostatic cancers, it is very difficult to obtain cancer cell lines which can be transplanted in immunodeficient animals (such as athymic mice) and only a few xenografts are currently available, some of which, like PCV-82, LuCaP 23, CWR-22, are androgen-dependent or sensitive. These models can be used to study host-tumour interactions as well as endocrinological interactions, stroma-tumour cell interactions, and to analyse molecular phenomena related to stages of hormone dependence and hormone resistance. In vitro and in vivo models of metastatic prostatic cancer have also been developed and appear to have a crucial impact on the understanding of metastatic mechanisms and new therapeutic approaches. This paper describes the main experimental models developed from human prostatic cancers, their main characteristics, their value compared to clinical cancers and some of the major studies conducted with these models. Due to the exponential progress in molecular biology techniques and oncogenetics, it appears essential to increase the number and diversity of experimental models of prostatic cancer in order to advance research concerning the crucial phenomena occurring during the course of this disease, from oncogenesis to currently incurable metastatic stages.

5% of ovarian cancers occur in a hereditary predisposition context. Clinical syndromes are defined by 3 or more cases of breast or ovarian cancers, or cancers from the Lynch-type II spectrum (colon, endometrium...) in one family branch. When the diagnosis is established, genetic counselling is provided to the kindred, a molecular diagnosis is undertaken for BRCA1 and BRCA2 genes, screening for ovarian and other at risk cancers is proposed, or prophylactic oophorectomy is proposed for at least 35 years old women without children conception projects.

Numerous structural lesions or disorders accumulate in DNA either spontaneously or following genotoxic stresses. Living cells have developed various strategies to eliminate most of these lesions so as to preserve a life-compatible genetic information. Several human diseases are associated to some DNA-repair processes. Analysis of cells derived from these patients has allowed the isolation of repair genes and the molecular analysis of lesions proofreading mechanisms. Most of these diseases are extremely severe, pointing out to the biological extent of repair systems, and are associated to genetic instability which frequently lead to high cancer proneness.

Since its recent discovery on chromosome 9p21 band, the p16INK4a/MTS1/CDKN2 gene has been reported as one of the most frequently impaired tumor suppressor genes (ranking second after p53) in a variety of malignancies, including acute lymphoblastic leukemias. In fact, the situation is likely to be more complex than expected: the gene has a very unusual status in that sense that it encodes two structurally unrelated but functionally similar proteins, p16INK4a and p19ARF. In this minireview, the present status of the gene is examined.

Type 1 neurofibromatosis considerably increases the risk of cancer development, particularly neurosarcoma. We report a case in a patient with chemosensitive metastatic neurosarcoma.

Primary mediastinal non-seminomatous germ-cell tumors (PMNSGCTs) are rare neoplasms that occur in young male adults. Incidence is evaluated about half that of extra-gonadal GCT. Their treatment is generally based on protocols used for testicular cancer, but with poorer results. Based on our experience of 40 patients with PMNSGCTs and data from the literature, we review here the clinical and biological data of these neoplasms. PMNSGCTs seem to constitute a specific entity, distinct from other GCT by the following criteria: true extra-gonadal origin, high incidence in patients with the Klinefelter's syndrome, over-representation of the yolk-sac component, poorer chemosensitivity and survival compared to other GCT, frequent occurrence of non-treatment related hematological neoplasia. The finding of an isochromosome of the short arm of the chromosome 12 in the leukemic karyotype is one of the strongest argument for a common origin in the yolk-sac component of the PMNSGCTs and their associated leukemia. Treatment of PMNSGCTs is still a challenge and should be conducted by a well-trained medical team.

Although several cytogenetic alterations have been associated with development of Wilms' tumor, a multigenic neoplasia, molecular mechanisms of its induction, development and maintenance remain to be elucided. In order to characterize these different steps we have developed a unique animal model of Wilms' tumor constituted by the MAV-1(N) induced avian nephroblastoma. This animal model led to the discovery in our laboratory of a new gene now (nephroblastoma overexpressed gene) which is overexpressed in all avian nephroblastoma. Expression of the human nov gene (novH), which is down-regulated by WT1, is also deregulated in Wilms' tumors. Nov characteristics suggest that it would play a role in the control of cellular proliferation and differentiation. Our observations also indicate that nov could be involved in the development of Wilms' tumors, and represent a marker of their differentiation state.

When N-myc copy number was assessed by molecular biology, it has been proven that an amplification of the oncogene was a bad prognosis in childhood neuroblastoma, and the same goes for DNA-diploidy. This study concerns the development of a biparametric flow cytometric analysis of 2 neuroblastoma cell lines (SK-N-SH and IGR-N-91), which exhibited respectively 1 and 60 copies of the N-myc oncogene. An indirect immunofluorescence technique allowed N-myc oncoprotein staining and an isotypic control was used to assess the threshold of specific fluorescence. Simultaneously, a double staining with propidium iodide gave the nuclear DNA content. For both types of cells, the level of N-myc expression was calculated as a fluorescence index (IF). IF for IGR-N-91 appeared 2.5 times higher than those of SK-N-SH. This fluorescence index increases significantly during the exponential growth of N-myc amplified cells, whereas it does not vary for SK-N-SH. During IGR-N-91 tumoral evolution, the cell line which derived from murine heart metastasis was the only one to show an increased IF. When applied to 10 neuroblastoma cell suspensions, this double staining showed an high IF for only 1 N-myc amplified case. A poor cell yield after tumoral dissociation and too much debris did not allowed the calculation of IF for half of them, which hampered a routine development of this technique.