Ovarian cancer is the fourth most common cancer in women. Its pronostic is dreadful and, in spite of numerous studies, the steps of ovarian carcinogenesis are unclear. Histologically, three sub-types of ovarian tumors (benign, borderline and invasive) are distinguished, suggesting the existence of a continuum. However, as each sub-type presents its own biologic characteristics, the hypothesis of the progression of a pre-neoplastic precursor (benign or borderline tumor) into an invasive tumor is still open to discussion. Numerous molecular biological studies have been conducted on ovarian tumors, with the aims of identifying their molecular abnormalities and better understanding the process of ovarian carcinogenesis. Synthesis of the published data (concerning oncogene amplification and/or surexpression, loss of heterozygosity, tumor suppressor gene inactivation, microsatellite instability) shows that there are numerous abnormalities, confirming the heterogeneity and the complexity of these tumors. Hence, it remains very difficult to draw a scheme of ovarian carcinogenesis. Nevertheless, in a near future the new technology of laser microdissection may improve the quality of the results and the study of early ovarian lesions. Indeed, with this technique, it becomes possible to isolate well-defined and homogeneous cell populations and to study small or architecturally complex (surface lesions) tumors. In the next years, the results obtained may allow the identification of early events of the ovarian carcinogenesis and the development of diagnostic and therapeutic tools.

Women identified or suspected as carriers of mutations in BRCA1 or BRCA2 susceptibility genes have a high risk to develop an early breast cancer and thus, require appropriate management. Some consensus guidelines were provided for women at hereditary risk and two possible strategies of prevention are suggested: breast cancer screening and prophylactic surgery. We present the French recommendations for breast cancer surveillance and discuss the justification, indications and modalities of mammographic screening. Screening by annual mammography is recommended from age 30 years in experienced centers, in association with semi-annual clinical breast examination from age 20 years. These recommendations apply to women who were identified as carriers of a cancer-predisposing mutation of BRCA1 or BRCA2 genes. In families for whom any mutation of the two genes could be identified, the same modalities apply also to women with a higher probability than 25% of being a carrier. We present here an illustration of the calculation of such probabilities from two example-pedigrees.

The great majority of breast cancer cases are not associated with a mutated gene of high penetrance such as BRCA1, BRCA2 and TP53. Genes of low penetrance, frequently mutated in the general population, might play an important role in breast cancer development. The ATM gene, which encodes the ATM protein, mutated in the disorder ataxia telangiectasia (AT) could be such a susceptibility gene. Indeed, 1% of the general population is estimated to be AT heterozygote and females have an increased risk of developing breast cancer. The ATM protein is involved in the signalling pathway of DNA double-strand breaks. Studies on its expression in normal breast tissues have shown that ATM is expressed in the epithelial cells of breast ducts, but not in the myoepithelial cells. In sclerosing adenosis, a benign lesion of the breast, the ATM protein is expressed in both cell types whereas its expression is absent or reduced in tumour epithelial cells in about 30-50% of invasive carcinomas. Moreover, the study of the p53 status in some of these tumours has revealed that the ATM/p53 signalling pathway is frequently altered either by a very low ATM expression or by the presence of a mutated p53. It remains to be determined whether alterations in the expression of other proteins also involved in this DNA damage signalling cascade are specifically associated with breast cancer development and/or a radiosensitive phenotype seen in some breast cancer patients after radiotherapy.

During the past ten years, the improvements of our understanding of cellular signal transduction pathways provide new targets for drug therapies. Chronic myeloid leukemia (CML), a malignant hematopoietic stem cell disorder, is characterised by an acquired genetic abnormality: the Philadelphia chromosome (Ph) and its molecular counterpart, the oncogene BCR-ABL. The latter, which is translated in an active BCR-ABL protein, exhibited a deregulated tyrosine kinase activity inducing malignant transformation. Produced from the 2-phenylaminopyrimidine class, a novel synthetic inhibitor, identified as CGP57148 (STI571), inhibits tyrosine kinase activity of c-ABL, BCR-ABL, PDGF-R and c-kit at micromolar concentrations. It suppresses the proliferation of the majority of BCR-ABL positive cell lines. The phases I-II clinical trials in CML have demonstrated promising results, especially in the chronic phase of the disease. STI571 is an original therapeutic approach which may be used as a model for the development of other drugs in cancer.

1,120 children were included in protocol FRALLE 93 from june 1993 to september 1998. Disease Free Survival for the all protocol is 78% +/- 3 and overall survival 83% +/- 3. Various clinical and laboratory features at the time of diagnosis have been correlated with prognosis. They provide a potential mean to stratify patients into treatment subgroups according their relative risk of treatment failure. The identification of these prognostic factors has been an essential element in the design of current therapeutic trials. Prognostic characteristics of childhood ALL include: age, white blood cell count, tumor burden, cytogénétics (chromosome count and chromosomal translocation), immunophenotype and early response to treatment. Molecular biology has been the revolution of the last two decades permitting the cloning of the genes involved in the leukemic process. Finally the new molecular techniques allow a sensitive diagnostic approach to minimal residual disease (MRD). The better detection of MRD must allow a more rational basis for therapeutic intensification for a subset of poor responder patients. A decrease in therapy of very good responders can also be envisaged.

Inherited conditions predisposing to cancers have long been recognized. Specific medical recommendations have more recently been proposed to avoid the development of advanced cancers in such high-risk families. The identification of the first genes involved in monogenic dominant cancer-prone conditions have opened the ways to their predictive diagnosis in asymptomatic members in at-risk families. The development of such procedures has required specific involvement for clinicians and molecular geneticians. The example of familial predispositions to colonic cancers has been chosen to illustrate the practical issues, and to help the physicians in charge of at-risk families to offer their patients an access to these emerging possibilities in cancer prevention. A table summarizes the practical issues requested to refer a family and initiate the procedure of molecular testing.

Our knowledge in the genetic basis of hereditary human cancer has improved over the last 10 years. Molecular diagnoses have become feasible in major hereditary cancer-prone syndromes, as well as in other hereditary diseases in which cancer appears as symptoms or complications. The major cancer-prone syndromes are described here with a table summarizing the links between various cancer types and the genetic syndromes to which they could belong. Clinicians should be aware of these new diagnostic tools. Specific consultations in oncogenetics are being settled to help clinicians and patients in the course of establishing molecular diagnoses, and providing guidelines for a better surveillance of high-risk persons.

After a quarter century of rapid advances, cancer research has generated a rich and complex body of knowledge, revealing cancer to be a disease involving dynamic changes in the genome. Several lines of evidence indicate that tumorigenesis in humans is a multistep process and that these steps reflect genetic alterations that drive the progressive transformation of normal human cells into highly malignant derivatives. The barriers to development of cancer are embodied in a teleology: cancer cells have defects in regulatory circuits that govern normal cell proliferation and homeostasis. This review concern the description of novel capabilities acquired during tumor development.

The atypical teratoid rhabdoid tumor is a rare brain tumor of childhood. We report a congenital case, revealed by peripheral facial palsy. This polymorphous tumor consisted of rhabdoid cells associated with areas of primitive neuroectodermal tumor. The immunoreactivity for the three proteins vimentin, epithelial membrane antigen and smooth-muscle actin was suggestive of rhabdoid tumor. Genetic study showed a homozygous mutation in the tumoral DNA and a constitutional heterozygous mutation, as it was demonstrated in atypical teratoid rhabdoid tumors and in renal and extra-renal rhabdoid tumors.

The Li-Fraumeni syndrome (LFS) is an inherited form of cancer, affecting children and young adults, and characterized by a wide spectrum of tumors, including soft-tissue and bone sarcomas, brain tumours, adenocortical tumours and premenopausal breast cancers. In most of the families, LFS results from germline mutations of the tumor suppressor TP53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. Recently, germline mutations of hCHK2 encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The LFS working group recommendations are the following: (i) positive testing (screening for a germline TP53 mutation in a patient with a tumor) can be offered both to children and adults in the context of genetic counseling associated to psychological support, to confirm the diagnosis of LFS on a molecular basis. This will allow to offer to the patient a regular clinical review in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 indications for positive testing are: a proband with a tumor belonging to the narrow LFS spectrum and developed before age 36 and, at least, first- or second-degree relative with a LFS spectrum tumor, before age 46, or a patient with multiple primary tumors, 2 of which belonging to the narrow LFS spectrum, the first being developed before 36 or a child with an adenocortical tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors the prognosis of some tumors, the impossibility to ensure an efficient early detection and the risk for mutation carriers to develop multiple primary tumors justify that prenatal diagnosis might be considered in affected families.

Minimal residual disease (MRD) can be easily studied in hematological malignancies by analyses of various fusion transcripts or tumor-specific immunoglobulin heavy-chain or T-cell receptor rearrangements as markers of disease. Correlation between MRD and prognosis has been extensively investigated mostly in acute leukemia and chronic myeloid leukemia. Quantitative aspect seems an essential criterion but the current absence of standardization makes difficult clinical decision according to MRD results. Development of real time quantitative PCR techniques would probably overcome these limitations. Only follicular non-Hodgkin's lymphomas are currently routinely analyzed using BCL2-JH PCR but signification of results obtained in complete remission remains uncertain. Analyses of tumor-specific immunoglobulin heavy-chain or T-cell receptor rearrangements allow physiological study and evaluation of bone marrow purgin system efficacy but are of limited interest in current clinical practice.