Microsatellite instabilities (MIN) represent a new type of mutation characterized by genomic instability (or replication error phenotype, RER+). First identified in sporadic and familial colorectal tumors, the RER+ phenotype has been sought in multiple types of cancers. Thus, two types of instability mechanisms have been shown: one due to inactivation of the mismatch repair system (phenotype RER+) and a second still unclear (instability of tri- and tetra-nucleotide repeats). In both cases, MIN seem to be the reflect of a new tumorigenesis pathway. In the context of mismatch repair defect, numerous observations show that, although instabilities seem to be random, they play a direct role in the tumoral process by altering genes that control cell growth and apoptosis. Today, MIN, as well as the detection of mutations in the DNA mismatch repair genes, can be used as diagnosis tools in oncology and provide usefull indications to adapt the chemotherapy to the disease.

The adenomatous polyposis coli (APC) gene has been found to be mutated during the development of sporadic colorectal cancers as well as in familial adenomatous polyposis (FAP). These conditions result from initially somatic and germ line mutations respectively. In both cases, the expressed protein is truncated at its carboxyterminal region. Investigations into the role of wild-type APC have led to a better understanding of the importance of mutations in the genesis and progression of adenomas. APC was shown to regulate cell growth and cell death, to bind beta-catenin, and to colocalize with microtubules. APC truncation was therefore hypothesized to alter cell multiplication and cells are no longer able to undergo apoptosis. Owing to its beta-catenin binding, APC can modify the pool of beta-catenin which is in part utilized in the assembly of adherens junctions and in nuclear signalling. Truncated APC is unable to regulate this pool thereby altering adhesion and cell signalling. Finally, APC involvement in microtubule-dependent locomotion may explain some changes in cell movement which are observed in adenomas. The establishment of murine mutants and of normal and malignant intestinal cell cultures have allowed to assess biochemical and physiological properties of APC and its putative role in the genesis of colorectal carcinogenesis. Moreover, these experimental models have suggested a variety of possible therapeutic approaches.

Lipoblastoma is a rare type of benign tumor occurring in infants. We report a case of mesenteric lipoblastoma with histologic, electron microscopic and cytogenetic studies. The microscopic features of this tumor including lipoblastic proliferation and prominent immature capillary beds were typical of lipoblastoma. Cytogenetic study showed a karyotype 46,XX, inv (8) (p 21.1; q 24.2). We discuss the usefulness of cytogenetic study associated to fluorescent in situ hybridization, in the diagnosis of the lipoblastic tumors, i.e. myoxoid liposarcoma and lipoblastoma.

The ERBB2 (HER-2/neu) protooncogene encodes a transmembrane protein with an intracellular tyrosine kinase activity. It is principally activated by gene amplification and its product, the erbB2 protein, becomes oncogenic when overexpressed. Quantitative PCR is both a simple and reliable method for the evaluation of ERBB2 activation, whereas immunoenzymatic methods allow quantitative determination of erbB2 protein in tissue and sera. ERBB2 amplification and/or surexpression is actually recognized as a prognostic factor in breast cancer and would be predictive in the therapeutic response. It might lead also to new therapeutic modalities using specific targeted drugs.

Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant inherited disorder characterized by tumors of the parathyroids, endocrine pancreas, anterior pituitary, thymic, bronchic and digestive neuro-endocrine tissues and adrenal glands. The MEN1 gene has been recently cloned by two independent groups. The function of the protein encoded by the MEN1 gene is unknown until now. Germline mutations associated to the diseases in MEN1 families are distributed throughout all the open reading frame, suggesting the absence of founder effect. No consistent genotype-phenotype correlations have been yet recognized. Further studies on the functional domains of the MEN1 encoded protein could be useful to relate clinical expression of the disease with each type of mutation.

Bladder cancers display different forms from superficial to aggressive tumours with muscle invasion. Many studies on this disease have been carried out in order to better understand the molecular mechanisms involved in its progression. Two loci are frequently associated with bladder tumorigenesis. The chromosome 9 lesions seem to be earlier involved in carcinogenesis, and suggest the presence of a tumour suppressor gene, and on the other hand the TP53 gene mutations (17q13.1) are later but take place in tumour progression. These alterations could be used as early diagnosis tool in bladder tumours and orientate the search for the bladder cancer gatekeeper gene(s).

ACTH-secreting non-pituitary tumors are a rare cause of Cushing's disease. We report the clinical course, prognostic aspects and molecular analysis data in three patients for whom the diagnosis was confirmed but who had variable clinical features and laboratory results.

Ataxia-telangiectasia is a rare recessive disorder which, among other clinical signs, is characterized by an extreme sensitivity to ionising radiation. Cells isolated from AT patients show radioresistant DNA synthesis and this has lead to the hypothesis that the product of the genetic determinant of AT may play a role in the detection, signalling or repair of double stranded DNA breaks. The gene to AT, called ATM has been recently cloned and characterized. It codes for a large RNA transcript of 13,000 bp of which a 3,500 aa protein is translated. The gene itself covers 150 kb, spread over 64 exons. The amino acid sequence has revealed the existence, at the carboxyterminal end of the protein, of a domain presenting homology to PI-3 kinase. This characteristic has allowed the description of a new family of nuclear protein, in yeast, drosophila an human, functionally involved in DNA damage signalling. It is interesting to note that a vast majority of mutations described in AT patients lead to the truncation of the protein and consequently to the elimination of the PI-3K domain, thus suggesting an important role in the normal function of the protein. An important question linked to AT mutation concerns the cancer risk associated to heterozygous mutations. It is well established that AT patients, homozygous for the mutation, present a 100-200 fold increased risk of cancer. Epidemiological studies have described a 3-5 fold increase risk of cancer (particular breast cancer in women) associated to the heterozygous mutation. Knowing that the incidence of the heterozygotes can be estimated to range 0.5 to 1% in the general population this question is of great importance in terms of public health.

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.