Some common human tumors are characterized by inactivating alterations of mismatch repair (MMR) genes that lead to an inability to recognize and repair errors that occur during DNA replication. These alterations are either inherited in the so-called hereditary non polyposis colorectal cancer (HNPCC) syndrome or can occur sporadically in 10-15% of colorectal, gastric, or endometrial tumors. Because of their repetitive nature, microsatellite sequences are particularly prone to mutation in tumors with MMR deficiency. Thousands of microsatellite alterations accumulate in MMR deficient cancers and these are referred to as MSI-H tumors (high level of microsatellite instability). MSI-H tumors have different clinicopathological features compared to cancers without this phenotype, and the repertoire of genetic events involved in their tumoral progression is also thought to be different. Many of the genetic alterations observed in MSI-H tumors affect nucleotide repeat tracks contained within genes thought to have a putative oncogenic function. These alterations are believed to play an important role during MSI-H carcinogenesis, since they can be either inactivating or activating events that are selected for in a recessive or dominant manner. We provide here an overview of the genetic changes that occur in MSI-H tumors and that appear to constitute a new genetic mutator pathway leading a normal cell to become malignant.

Melanoma frequency increases. Conventional antitumoral treatments fail. Gene therapy for metastatic melanoma is studied in 17 phase I-II clinical trials. ACTUALITES ET POINTS FORTS: Sixteen use cytokine genes. These studies are heterogenous as far as methodology is concerned. Gene therapy clinical tolerance is acceptable. Security is rarely discuted. In these studies overall response rate is 8%, with histological complete responses.

Breast and ovarian cancer occur more frequently in young women with BRCA 1 &2 mutations (respective cumulative risks from 37 to 85% and 10 to 20%), and raise specific gynaecologic problems as prophylactic surgery and hormonal treatments. Two medical files from 2 sisters with BRCA 1 mutation (exon 11) are presented and the authors discuss the therapeutic options chosen. BRCA 1 & 2 tumour suppressor genes seem to play a major role in the repair of cellular damages inducing by the estrogenic proliferative signal. The prophylactic mastectomy is effective for the breast cancer prevention but its acceptance is low. The oophorectomydecreases the ovarian risk (knowing the occurrence of peritoneal carcinomatosis in 1.8% of cases) and currently the breast cancer risk (RR = 0.47) by the hormonal privation: the hormone replacement therapy does not seem to increase the breast cancer risk in the small series published. The HRT is possible in women with BRCA mutation under medical supervision and if the doses of hormones are light. The first results concerning the chemoprevention by Tamoxifen are encouraging (RR = 0.38) in these patients, but more studies are needed. The oral contraception exerts an uncertain effect against ovarian cancer, but possibly enhances the breast cancer risk in this group of women (RR = 3.3). The management of women with BRCA mutation is varying according to their own priorities, which can change during their life.

The clinical, hematological, and cytogenetic data from a 4 year-old child with acute myeloid (AML-M1) and basophilia is reported. Interestingly, cytogenetic investigations revealed the presence of the translocation t(6;9) (p23;q34). This abnormality is rare and associated with myelodysplastic syndromes or with subtypes of acute myeloid leukemia (M1, M2, M4, M7), usually with preceding or underlying myelodysplasia. The prognosis is poor, without response to chemotherapy regimen alone. Allogeneic bone marrow transplantation appears likely to be a more appropriate treatment.

Medulloblastoma is the most frequent malignant brain tumor of the posterior fossa in children. As prognostic factors for this disease are not well-established, it seemed important to identify genetic features in these tumors. We present data provided by recent studies on conventional cytogenetic, molecular cytogenetic and molecular genetic in correlation with prognosis in these tumors.

The development of oral and head and neck squamous cell carcinomas occurs in relation with multiple events including mainly: loss of cycle cell control, evasion from apoptosis, telomerase reactivation. Complex interactions between a set of molecules, cell cycle proteins, tumour suppressor genes, oncogenes and the telomerase, occur in the multiple step process of carcinogenesis. The 2 main ways of control of the cell cycle rely on 2 tumour suppressor genes: the P53 gene and the retinoblastoma gene or RB gene. One of the regulation pathways or the 2 regulation pathways are disabled during the development of oral and head and neck squamous cell carcinomas. Most of the time, the inactivation of the P53 pathway results from a loss of function of the p53 protein, secondary to mutation and/or deletion of the P53 gene; It may also result of the amplification of the MDM2 gene and of the inactivation of the arf protein. The RB pathway leads to cell proliferation by loss of the p16 protein, by amplification of the cyclin D1 gene and less frequently by mutation of the RB gene or loss of the retinoblastoma protein. In India and South-East Asia, the activation of RAS and MYC oncogenes appears to be related with the presence of specific carcinogens in snuff and tobacco. By blocking apoptosis, the Bcl2 protein seems to increase the resistance of tumours to radiotherapy and chemotherapy.

Several studies have reported the important role played by telomerase, an enzyme which maintains the length of telomeres, during carcinogenesis. The objective of this study was to detect telomerase activity by semiquantitative in situ methods and to quantify expression of the hTERT subunit in a group of bladder cancers in order to assess its diagnostic and prognostic value.

The aim of this work was to pinpoint familial breast and/or ovarian cancer risk. Clinical cancer genetics include: diagnostic cancer genetics, cancer genetic counseling and management of women at high risk of developing breast and/or ovarian cancer.

At the present time, there is no reliable laboratory marker for the diagnosis and prognosis of clear cell renal cell carcinoma (RCC), while about 20% of small tumours detected by modern imaging techniques are benign and the clinical course is difficult to predict with considerable differences for the same stage and same grade. The molecular identification of clear cell RCC cells could satisfy these new requirements in the context of diagnosis of atypical or small renal tumours, allowing a more refined prognostic assessment, which is currently uncertain. Some of the antigens used for molecular diagnosis of clear cell RCC, such as cadherin-6, are present in the normal kidney, while others are newly formed antigens (TuM2PK, MN/CA9, CA12, calpain) or ectopic (PSMA, PSA, KLKI, cytokeratin 7 vimentin) or induce abnormal glycosylation (sialyl Lewis'X, galectins) indicating the malignant nature of the cells. The tumour's capacity for progression is related to dysregulations of the cycle (ras, Pax2, Tiam 1, waf/p21), division (tetracyclines, MIB1, PCNA, Nor Ag), apoptosis (bcl2, p53, CD95/Apo1), and the capacities for tissue invasion (proteases), disorganization (cadherin, catenins) or nidation (ICAM-1, CD44). Finally, chromosomal anomalies (mutations, translocations) also occur. MN/CA9, cadherin-6, vimentin, mucin 1 and DNA content are particularly useful for the diagnosis and/or prognosis of clear cell RCC. These markers can be analysed by extremely sensitive cytometric (flow cytometry, plate cytometry) or molecular methods (RT-PCR, in situ hybridization). These techniques lower the limit of detection of tumour cells in biological products (aspiration cytology, microbiopsy) and eventually in circulating blood. Proteomic and genomic methods (biochips) should considerably accelerate research in this field leading to the development of routine clinical applications.

Banding karyotype is a routine technique, which allows the identification of numerous aneusomy and/or aneuploïdy in congenital diseases and cancers. However, this analysis fails to detect small or complex chromosome rearrangements. Molecular cytogenetic techniques like fluorescence in situ hybridization (FISH) analysis can overlap these limitations. Particularly, multicolor karyotyping by spectral karyotyping (SKY) may rectify or precise the conventional karyotype results. With two examples, we present here, the principle, the indications and the limits of this technique for constitutional and cancer chromosomal abnormalities characterization. Moreover, we present an easy way to build efficient sky probes with a best sensitivity than the probes classically used.

Chronic Lymphocytic Leukemia (CLL) most commonly arises from a malignant clone of B cells with a characteristic phenotype, an autoreactive activity and an increased resistance to apoptosis. It is far from uniform in presentation and clinical course. About one-third of patients never require treatment and have a long survival; in another third an initial indolent phase is followed by progression of the disease; the remaining third of patients have aggressive disease at the outset and need immediate treatment. During recent years the development of biologic markers has allowed a better definition of prognosis in CLL. Serum levels of beta 2-microglobulin, LDH, and soluble CD23 can help predict disease activity, but the presence in the leukemic B cells of cytogenetic abnormalities like 11q or 11p deletions, the presence of the CD38 marker or somatic mutations in the immunoglobulin heavy chain genes are better predictors of rapid progression and survival. These recent results could suggest that there are two types of chronic lymphocytic leukemia: one arises from relatively less differentiated (immunologically naive) B cells with unmutated heavy chain genes, and has a poor prognosis; the other evolves from more differentiated B cells (memory B cells) with somatically mutated heavy chain genes, and has a good prognosis. However, all CLL patients share a same morphology, phenotype and overexpression of the bcl-2 and p27Kip1. In addition, recent data derived from gene expression profiling analysis failed to clearly distinguish unmutated and mutated cases and favor the view that all cases of CLL have a common cell origin and/or a common mechanism of malignant transformation.

The pace of genome sequencing has been tremendously accelerated during the last few years leading to the determination of dozens of entire bacterial genome sequences in addition to several eukaryotic genome sequences and to the publication in 2000 of a draft of the human one. Nowadays scientists have to face a new challenge that corresponds to the elucidation of the function(s) of the thousands of genes uncovered by sequencing. Obviously this task will necessitate a large panel of methodologies. Since its domestication, dog has been the subject of intense breeding and selection practices that result in the creation of many breeds that differ one from the others by a huge variation in shape, size, coat colour, aptitude. Unfortunately these breeding practices along the selection of specific alleles governing those characters have co-selected various deleterious or morbid alleles and nowadays most of the canine breeds suffers from many different diseases of genetic origin. In addition many breeds have developed susceptibility toward many diseases very often similar to those affecting humans such as cancers, heart diseases, allergies.... In this paper we present arguments in favour of the utilisation of the canine model to sort out through linkage disequilibrium studies the phenotype/genotype relationship as an aid to understand the function(s) of the thousands of genes uncovered by sequencing.

Despite the fact that multiple myeloma is a unique entity, defined by the accumulation of malignant plasma cells, a marked heterogeneity is observed among patients (regarding biological and clinical presentation, response to treatment, or survival). Current prognostic parameters are poor predictors of response to therapy and of survival in individual patients. The application and analysis of DNA microarrays to plasma cells provide an overview of gene expression programs generated by these cells in normal and pathological conditions. Genes potentially involved in transformation process have been identified by gene profiles comparison between myeloma samples, normal plasma cells from various tissues, pretumoral plasma cells and immortalized plasma cells. We can speculate that in a near future gene expression-based classification will be used as a molecular prognostic indicator.

The analysis of biological processes has been revolutionized by the emergence of the DNA array technology. As cellular biological events are controlled by gene expression, their modulations are markers of the cellular activity. These modulations can be indicative of either a physiological process or a pathological one. Monitoring of the expression levels of thousands of genes simultaneously, the expression profiling method is based upon comparative studies where the identification of the differentially expressed genes in two samples is aimed. The two samples under study may be compared temporally or following drug treatment, they may also originate from different sources, e.g. normal versus pathological samples. In that case, gene expression profiling is conducted for diagnostics purposes or therapy monitoring, and offers an opportunity to identify new drug targets. Using different examples, we describe the potentialities of this approach in oncology.

A group of 139 patients with de novo acute myeloid leukemia were investigated to determine the prognostic significance of karyotype on early death, complete remission, continuous complete remission and survival. There were 27 children and 112 adults. Mean age was 32 years. t(15;17) was found associated with a high rate of early death and a diploid karyotype with long continuous complete remission. The presence of a structural change was predictive of shorter survivals. The study of the prognostic impact of recurrent anomalies reveals a good prognostic impact for normal karyotype (1 year survival probability: 40%), followed by t(8;21) (1 year survival probability: 24%), and by t(15;17) (1 year survival probability: 9%).