We studied the mechanisms of colon and rectal carcinogenesis by analysing in a series of 83 rectal tumors the prevalence of the two tumor types characteristic of colon cancer, i.e., the LOH+ type, defined by p53 and APC mutations (studied by DGGE and protein truncation assay), and the RER+ type, which is characterized by the instability of some mononucleotide repeat microsatellites (Bat 25 and Bat 26). Additionally, we analyzed the occurrence of Ki-Ras mutations (direct sequencing).

Uncontrolled proliferation is the characteristic of cancer. Several kinds of genes control the cell cycle: oncogenes, tumor suppressor genes, and genes implicated in apoptosis or survival. Two major pathways of control are frequently disrupted in human cancer. The first one is the RB pathway with inactivation of the RB protein (retinoblastoma protein), either by alteration of the retinoblastoma gene itself, or by genetic alterations of the genes implicated in RB phosphorylation. The second one is the inactivation of the p53 protein. Both of these abnormalities are described in human lung carcinoma but differ according to histologic subtype.

We observed the cases of two young women who both developed esophageal and perineal tumors successively. The esophageal component usually is the first manifestation. Esophagectomy, with or without gastrectomy is generally required. The genital affection involves the periclitoridian region, the minora and majora labia. Tracheobronchial localization is less common, but it may be lethal due to bronchospasm. An association between diffuse leiomyomatosis and Alport syndrome is not fortuitous. Recently, molecular biology has enabled to understand the combination of the two pathologies by showing the presence of a deletion on adjacent X chromosome genes, COL4A5 and COL4A6, which are involved in the synthesis of type IV collagen fibres. Leiomyomatosis and Alport syndrome are transmitted as X-linked dominant traits. Women with diffuse leiomyomatosis transmit Alport syndrome. An antenatal diagnosis can be proposed for such patients.

New technologies in molecular biology will allow the improvement of screening, diagnosis and prognosis of colorectal cancer patients. For example the determination of germline mutation in APC or in mismatch repair genes in patient with familial adenomatous polyposis or with HNPCC is now possible. The clinical surveillance can be restricted to the patients with these germline defects. More over the knowledge of somatic genetic alterations in colorectal cancer cells seems to be useful in the determination of prognosis of these patients or in order to predict the chemotherapy response.

9p21 chromosomal region contains p15INK4b and p16INK4a genes which regulate G1 phase of the cell cycle by inhibition of cyclin-cyclin dependent kinases. The p19ARF protein is translated from an alternative transcript of the p16INK4a gene and regulates G1 and G2 phase of the cell cycle by degradation of the MDM2 protein. p16INK4a and p15INK4b gene homozygous deletions occur mostly in acute lymphoblastic leukemia, ATL secondary to HTLV1 infection, and some lymphoma. Point mutations of p16INK4a or p15INK4b gene seem to be extremely rare, however selective methylations of the p15INK4b or p16INK4a promoters are frequently found in myelodysplastic syndromes and acute leukemias, or lymphomas and myelomas respectively. These data demonstrate that inactivation of gene of the 9p21 region is currently the main molecular event found in hematological malignancies.

The understanding of the mechanisms responsible for the emergence and evolution of cancers has been in constant progress due to advances in molecular biology. Today it allows to conceive therapeutic alternatives to conventional cytotoxic chemotherapy. Among these, differentiation strategy, which aims at reinducing tumour cells towards a normal phenotype, has known a first clinical application with the use of retinoic acid in acute promyelocytic leukemias. Anthracyclines, traditionally employed in cytotoxic chemotherapy, present also a high potential of differentiation. Their mode of action takes place via the activation of transcription factors, which are proteins that are able to modulate the expression of genes by fixing to regulatory sequences of DNA. These observations therefore allow us to foresee a new pharmacology based on transcription factors for the treatment of cancers.

Alterations in the p53 gene are less common in hematological malignancies (10 to 15%) than in solid tumors, and usually consist in point mutations, which can be readily detected using SSCP or ICC. In most cases (except in non-Hodgkin's lymphoma) there is a close correlation between point mutations and a positive ICC. In myelodysplastic syndromes, acute myeloid leukemia, chronic myeloid leukemia, and chronic lymphoid leukemia, point mutations affecting one allele are accompanied with deletion of the other allele. The complete absence of the p53 gene in these conditions probably explains the poor prognosis and resistance to chemotherapy in these patients. In contrast, in the L3 form of acute lymphoid leukemia and Burkitt's non-Hodgkin's lymphoma, punctual mutations are common (30%) and rarely accompanied with deletion of 17p. These data confirm the key role of p53 in the induction of apoptosis after chemotherapy and support the need for developing tools for transferring the p53 gene into malignant cells with the goal of restoring chemosensitivity.

Transitional cell carcinoma of the bladder is heterogeneous and unpredictable. Tumor with similar clinicopathological parameters display different progression patterns. There is a need for a better management of these lesions, adapting the therapeutic load to tumor aggressiveness. Among various molecular abnormalities associated with tumor progression, analysis of p53 gene and/or p53 gene product, appears as a critical event. p53 mutation is observed in 34% of cases. Nuclear overexpression of p53 protein by mean of immunohistochemistry on tissue specimens and p53 gene mutations detectable on bladder washings may in the future implement histopathological and cytological analysis on routine preparations. Methods of standardisation and comparison between markers, are necessary in order to plan prospectives studies. These data strongly suggest that p53 gene and gene product alterations may be used as a clinically relevant tumor marker for bladder cancer.

Mutations of the p53 gene have been found in 380 of the 768 tumors (49.5%) included in the eight largest published series of colorectal cancer. Most point mutations of p53 change the conformation of the gene, and by stabilizing it make it detectable by immunohistochemistry. However, studies using both tests for p53 mutations and immunohistochemical methods found that the results of these two approaches were concordant in only 68% of cases. Conflicting data have been reported regarding the prognostic significance of positive p53 staining. Presence of a mutation is generally believed to indicate a poor prognosis.

Germline mutations of the p53 gene are associated to the Li-Fraumeni, a rare autosomal dominant syndrome characterized by 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 p53 mutations have been identified in approximately 50% of the families with the Li-Fraumeni syndrome, and in families which only partially fulfilled the definition of the syndrome. Germline p53 mutations are mostly missense mutations, located between exon 5 and exon 8, within the DNA-binding domain of p53 and these mutations inactivate the transcriptional activity of the protein. In tumours, the wild-type allele is usually lost, which indicates, that p53 inactivation fits the Knudson model. Identification of a germline p53 mutation in an affected subject allows to establish the diagnosis of the Li-Fraumeni syndrome on a molecular basis and screening for germline p53 mutations may be performed 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. In contrast, the clinical benefit of identifying germline p53 mutations carriers in affected families, considering the wide spectrum of tumours associated to this syndrome, remains to be established.

The mdm2 cellular protooncogene is involved in many human tumors where it has been shown to be overexpressed, including sarcomas, osteosarcomas, gliomas and others. The Mdm2 protein is believed to be oncogenic by binding and inactivating the p53 and Rb tumor suppressor gene products and by activating the E2F-1/DP-1 transcription factors, thus promoting the G1 to S phase transition. The mdm2 gene is activated transcriptionally by p53, thus forming an autoregulatory negative feedback loop. This feedback loop is important in normal cells and when cells are exposed to various genotoxic agents. By activating its own negative regulator, p53 would signal the cells to resume proliferation after a p53-mediated G1 arrest in response to DNA damage. The review aims to detail the functions of Mdm2 in normal and tumor cells. We also discuss several recent data suggesting that Mdm2 may exhibit activities unrelated to its well known function as a negative regulator of p53 activities.

Experimental carcinogenesis has, until recently, relied on the use of animal models in which the tumorigenic process is distantly related to that observed in humans. More recently the use of transgenic mice has open new opportunities but has also revealed two limitations: firstly, some of the most prominent tumors observed in genetically predisposed humans are not observed in the corresponding mice; secondly, in most instances mice carrying a totally inactivated tumor suppressor gene die early during development. To overcome these difficulties we have developed a modular transgenic mouse model for the tissue-specific inactivation of the neurofibromatosis type 2 (NF2) tumor suppressor gene. Mutations are induced by breeding mice carrying different combinations of null and targeted but functional alleles. The regulated induction of tissue-specific somatic lesions is achieved by in vivo activation of site-specific recombination with Cre recombinase that mediate excision of sequences at specific recognition sites (loxP). In this conditional knock-out model, an additional degree of sophistication enables to trigger the creation of defined somatic mutations not only in a tissue-specific manner but also at a time that is decided by the investigator. This approach is made possible by the development of inducible regulatory systems. This further development should provide excellent flexibility to analyse in detail the consequences of the occurrence in time of the different mutations that contribute to tumor initiation and progression.

Pancreatic carcinoma ranks fifth among the leading causes of cancer death in developed countries. Although the incidence of pancreatic cancer is about 10 per 100,000 inhabitants, the five-year overall survival is barely one to 4%. Few risk factors have been identified. Smoking increases the relative risk by 1.5, chronic pancreatitis by 26. Hereditary formes are rare.