Lymphomas are the most frequent haematological malignancies in France. Their histoclinical heterogeneity reflects their complex and combinatorial nature which remains poorly elucidated at the molecular level. Today, DNA arrays allow to tackle this diversity by measuring the mRNA expression level of thousands of genes simultaneously in one sample. Recent publications show the potential of DNA arrays to improve the prognostic classification of diffuse large B cell lymphomas and of Hodgkin's lymphoma, by identifying new tumour classes unrecognised by classical factors.

Polycystic ovary syndrome is the most common endocrine disorder in women of reproductive age. It is characterized by hyperandrogenism, chronic anovulation and it is often associated with hyperinsulinemia, insulin resistance and dyslipidaemia. The pathophysiology of polycystic ovary syndrome seems to implicate primary defects in ovarian steroidogenesis, influenced by environment, insulin action and obesity. Polycystic ovary syndrome is probably both a multigenetic and environmental disease. Knowing the genes of polycystic ovary syndrome would be helpful to develop therapeutics and prevention. Genes of gonadotrophins, steroid hormone synthesis and insulin resistance seem not to be directly involved, except perhaps the CYP 11 a gene. On the other hand, identification of the signal transduction pathways involved in these genes may provide valuable information that can be applied to other clinical manifestations of polycystic ovary syndrome (follicular growth arrest, insulin resistance, obesity and endometrial cancer...).

Tumor-associated angiogenesis is emerging as an important prognostic factor and represents a hopeful potential therapeutic target for the cancer treatment. Bladder tumors, as all solid tumors, require an active angiogenesis to support their growth and progression. The angiogenic phenotype observed within a tumor is determined in large part by the balance between stimulatory and inhibitory inputs to the endothelial cells. Clinically, the importance of the angiogenic response observed within a tumor should be considered as an independent prognostic factor for superficial as well as invasive bladder tumors. The analysis of the angiogenic response could in the future influence the therapeutic strategy. Angiogenesis also represents a promising new therapeutic target, and is at the moment intensively tested in experimental and clinical trials. In this article, we will first review the mechanism of angiogenesis, and then its implication in bladder cancer, and as a potential therapeutic target.

Colorectal cancer is the most common malignant tumor in the french population. This tumor represents 45% of the cancers of the digestive tract in female and 60% in male. It is one of the main problem in the field of Public Health but recent progress for research, prophylaxis and treatment have been performed. There are two different pathogenic pathways for colorectal cancer. In chromosomal instability a sequence of rearrangements leads step by step from normal to adenoma and to carcinoma. It is the common pathway observed in 85% of colorectal cancers, mainly localized in left colon. In genic nucleotidic instability loss of tumor-suppresor genes and activation of cellular oncogenes are the consequence of DNA mismatch repair system, which is controlled by several genes. The defect of DNA mismatch repair leads to a hypermutable state in which simple repetitive DNA sequences are specially instable. This is the basis for a test to demonstrate nucleotidic instability. This pathway is found in the remaining 15% of colorectal cancers which are mainly localized on right colon. A mutational inactivation of both alleles of APC gene is considered as an initial gatekeeper event although some cancers begin with a mutation in beta-catenin gene which has the same functional impact. APC expression plays central role in regulating the rate of beta-catenin degradation. Destruction of beta-catenin prevents its translocation into the nucleus where it promotes cellular proliferation. About 5% of colorectal cancer are developed in a high risk population, Familial Adenomatous Polyposis coli (FAP) or Hereditary Non Polyposis Colon Cancer (HNPCC). FAP is caused by a germline mutation in APC gene. Every cell harbors a mutation of an APC allele which insures that a large number of adenomas will occur once an inactivating event occurs on the other wild-type APC allele. The demonstration of a constitutional mutation in a family allows to limit the survey only to the carriers. The phenotypic expression (attenuated, profuse, associated with extra-intestinal lesions) is correlated with the site of the APC mutation. Thus the determination of this site occurs in the choice of the treatment. HNPCC is suggested on clinical and genealogical criterions (young age of onset of cancer, multiple family members affected with cancer in multiple generations, the association of certain tumors in an individual of family, multiple tumors). A biological test may be useful to demonstrate the nucleotidic instability (MSI: microsatellite instability). Constitutional mutations on the mismatch repair genes, mainly MSH2 and MLH1, cause HNPCC syndrome. Endometrial and urethelial malignant tumors are frequent in an individual or in the family. The proven or suspected carriers of mutations undergo colonoscopic surveillance every 1 to 2 years, starting at age 25. An anti-tumoral action of the non steroidal antiinflammatory drugs (NSAID) is now recognized. Firstly observed in animal models of colon cancer the suppressive action was demonstrated in patient with Familial Adenomatous Polyposis. From the results of several epidemiological studies the suppressive action can be generalized to common intestinal tumors. This effect is in relation with the cyclooxygenase 2 inhibition. Other independent pathways intervene: NSAID interfere with beta-catenin, decreasing its action on cellular division. The indication of NSAID and more specifically of COX2 inhibitors in the prophylaxis of colo rectal cancer are yet questioned. The results of trials in progress are expected.

Benign and malignant thyroid tumors constitute a wide range of neoplasias showing recurrent chromosome abnormalities. Cytogenetic studies of thyroid hyperplasias and follicular adenomas revealed hyperdiplo d karyotypes with a characteristic sequence of trisomies (7, 5, 12, 14, 16, 17, 20 and 22) starting with trisomy 7. Comparative genomic hybridization (CGH) findings on thyroid oncocytic tumors showed similar chromosomal gains with no difference observed between adenomas and carcinomas. Follicular thyroid carcinomas exhibit losses of 3p25-pter predominantly or of 22,13 and 1p segments. Formation of fusion genes PAX8 - PPARgamma1 caused by a t(2;3)(q13;p25) has been observed in several cases of follicular carcinomas only. Loss of chromosome 22 has been found most frequently associated with widely invasive follicular carcinomas. Activation of the RET protooncogene through chromosome rearrangements involving subband 10q11.2 represent the most common and specific genetic alteration in papillary thyroid carcinoma. Several chimeric genes resulting in the fusion of the tyrosine kinase domain of RET with the 5' sequences of different genes have been described. Germline mutations in RET are associated with medullary thyroid carcinoma in multiple endocrine neoplasia type 2 (MEN2). Cytogenetics of thyroid tumors, using conventional and molecular methods (FISH, CGH) demonstrated that particular chromosome aberrations may be related to the clinical behavior of these tumors and may provide informations for their diagnosis or prognosis.

Breast cancer is a major health problem. Clinical heterogeneity makes prognosis and sensitivity to treatment highly variable among patients. The recently developed cDNA array technology allows to analyse the expression of thousands of genes simultaneously. Results of the pioneering studies are promising: expression profiling of breast tumours using cDNA arrays seems able to identify new prognostic sub-classes unidentifiable using conventional parameters.

We describe an interphase FISH analysis for formol-fixed, paraffin-embedded tissue sections with commercial probes detecting the t(11;14)(q13;q32) in mantle cell lymphoma and the t(8;14)(q24;q32) in Burkitt's lymphoma. Staining of an adjacent section allowed identification of tumoral areas. The cut-off value was evaluated in reactive lymph nodes at 5% for both probes. An incomplete hybridization pattern was found in 18 to 26% of the nuclei but was always lower than the percentages of translocated cells in tumoral regions. A t(11;14) was detected in 4/4 mantle cell lymphomas and a t(8;14) in 2/3 Burkitt's lymphomas. Interphase FISH analysis of fixed-tissue sections is a reliable technique for the direct detection of lymphoma-associated translocations on routine histological material.

The twentieth century has witnessed the discovery of the various genetic alterations that drive a normal cell toward neoplasia. The challenge of the near future concerns the diagnostic of these alterations and their correlation with clinical parameters such as response to therapy or survival. It will be important to define, for each patient, a specific profile of the various alterations in order to improve and personalize the therapy. It is also essential to understand the various mechanisms of these alterations in order to develop new diagnostic procedures. Furthermore, the relation between genotype and phenotype is not straightforward and can be influence by various parameters such as the localization of the mutation, the alterations of other genes or the expression of modifier genes.

Immunohistochemistry (IHC) is a rapid morphological method that allows the detection of proteins involved in different mechanisms of cancer development. It is therefore a useful tool in the study of cancerogenesis. The best known example is the product of the p53 gene, a tumour suppressor gene which is altered in 50% of all human tumors. In fact, these p53 gene mutations lead to cell protein accumulation whereas the p53 product is not detectable in normal cells. This method also enables the detection of fusion proteins which result from chimeric transcript like WT1 in desmoplastic small round cell tumors, ALK in anaplastic large-cell lymphomas and FLI-1 in Ewing's sarcomas. On the contrary, gene inactivation can induce loss of immunostaining. hMLH1 and hMSH2, which are committed in DNA mismatch repair, can be altered in familial digestive carcinomas, such as hereditary non polyposis colorectal cancer. Thus IHC, which allows us to focus on the altered gene by loss of its product in tumoral cells, represents a good alternative to molecular analysis. IHC is also useful to detect the product of oncogene overexpression such as HER-2 in some breast carcinomas, which allows appropriate therapeutic protocols. Finally, IHC can be used in diagnostic, prognostic and therapeutic ends. Nevertheless, difficulties can be en- countered in the interpretation of the results. Therefore, IHC must be performed in quality control trials.

PCOS is the most frequent endocrine disorder of premenopausal women. The common clinical signs of PCOS are hirsutism, menstrual irregularities with chronic anovulation and a trend toward overweight or obesity. Diagnosis is based upon high plasma levels of androgens and the ultrasound image of polycystic ovaries. The high prevalence of PCOS at first degree female relatives suggest an important genetic component of this syndrome. Linking studies in sisters presenting phenotypical traits of PCOS and in their parents allowed the investigation of certain candidate genes presumed to be involved in the physiopathology of PCOS. The genes encoding enzymes involved in androgen synthesis, protein transducers of insulin signals and the paracrine regulating factors of gonadotrophins and ovarian function have been analysed. To date, no determinant gene mutation was reported. However, several loci were detected, especially a locus within the insulin receptor. Mutations or gene polymorphisms and their function remain to be identified. These research attempts should explain the physiopathology of PCOS and open new therapeutic perspectives. The usage of medication increasing the sensitivity to insulin action is an example of applying these particular aspects.

A new classification of lymphoma has been published in 2001 under the direction of the World Health Organisation. This classification is based on a consensus between experts in haematopathology, haematology and oncology involved in management of lymphoma. Around 40 entities are described on the basis of morphology, immunophenotype, genetic and clinical presentation. Lymphomas and lymphoid leukaemias are gathered because tumour masses and leukaemic phases are present in numerous entities. This classification differentiates B-cell lymphomas from T/NK (natural killer) cell lymphomas. Grading the different lymphomas into low grade or high grade is no more required in this classification.

Corticotroph adenoma is a benign tumor composed of adenohypophyseal cells; carcinoma with metastasis and ectopic adenoma have also been reported. In our pathological series, the frequency of this type of adenoma is 13% (250/1863 tumors removed between 1970 and 2001). Usually, corticotroph adenomas synthesize peptides derived from POMC maturation: ACTH, ss-endorphine, and ssLPH. In the great majority of cases, ACTH induces hypercorticism with clinical and biological signs of Cushing's disease. However, some tumors the pathologist identifies as corticotroph adenomas are not associated with clinical signs of hypercorticism (20% of the corticotroph adenomas in our series). Corticotroph adenoma is a basophilic or chromophobe tumor composed of cells which remain regulated by cortisol. This may explain the small size of this type of adenoma in 80% of the cases. In contrast, "silent" adenomas or macroadenonas which synthesize high-weight POMC are aggressive invasive tumors. Neurosurgery is indicated for the treatment of corticotroph adenoma. Recurrence is explained by incomplete removeal of the tumor. Peroperative studies may be necessary to find microadenomas. In some cases, the whole pituitary must be removed and cut in serial sections to find a tumor measuring<2 mm. In our opinion, the existence of corticotroph hyperplasia inducing Cushing's disease remains to be proven (we have never observed one). The pituitary origin of the tumor is based on its monoclonality. The general mechanism of tumorigenesis is known, but the specific factors involved and markers of aggressiveness remain to be discovered.

Many hormones exert their effects through specific nuclear receptors which belong to a superfamily of ligand-activated transcription factors. These receptors control target gene expression through the recruitment of different cofactors acting as transcription activation or repression mediators, generally as parts of multiprotein complexes. The importance and the role in physiopathology of these different cofactors only begin to be defined. Different types of alterations affecting genes coding nuclear receptor transcription cofactors have indeed been described in cancer. The most important examples are gene amplification that leads to overexpression and gene mutations or translocations introducing qualitative modifications. This paper aims at bringing together the corresponding literature and focuses on gene alterations observed in solid tumors.

The transcription factor NF-kappa B has attracted widespread attention among researchers. NF-kappa B displays some original characteristics including rapid regulation, the wide range of genes that it controls and its probable involvement in several diseases. In resting cells, NF-kappa B is kept in an inactive form in the cytoplasm where it is bound to a member of the I kappa B family of inhibitory proteins. NF-kappa B can be activated by exposure of cells to physiological as well as non physiological stimuli. Upon cell activation, the inhibitors are modified through site specific phosphorylations which target them for subsequent ubiquitination and proteolytic degradation by the proteasome. Removal of the inhibitor unmasks the nuclear localization signals on subunits of NF-kappa B. Free NF-kappa B moves to the nucleus where it binds to target DNA elements and activate transcription of genes encoding proteins involved in immune responses, inflammation or cell proliferation. NF-kappa B could be considered as a co-ordinating element in the body's responses to situations of stress, infection or inflammation. A tight regulation of NF-kappa B seems to be crucial since a dysfunction could promote pathogenic processes including AIDS (acquired immunodeficiency syndrome), rheumatoid arthritis and cancer. Additionally, it will be important to understand the exact roles for NF-kappa B in regulating apoptosis. NF-kappa B is now regarded as a good therapeutic target and the development of specific inhibitors should lead in the next future to novel therapeutics.

The population with Down's syndrome has a different cancer profile compared to the general population, even after taking into account issues of survival and ageing. Several solid tumours are unusually rare, whereas in contrast leukaemias are increased. In addition, few studies are available on this topic. We therefore decided to conduct a mortality study based on the INSERM national mortality statistics in France comparing over a 24 year period deaths from female breast cancer in the general French population with the cancer deaths in women with Down's syndrome. Only 5 deaths with Down's syndrome could be found compared to 68.98 expected based on national statistics. This clear reduction in risk agrees with other studies available in Down's syndrome patients. This observation could be partly explained by over expression of genes linked to gene dosage effects on chromosome 21, playing a role in cell growth, differentiation, survival and death. An additional protective effect could come from the marked and continued decreased exposure to oestrogens, starting in utero for women with trisomy 21 and lasting all over life.

The course of hepatitis B virus (HBV) infection may be influenced by the host immune response. A prospective study was carried out in ninety-eight subjects (mean age = 23 years) HBs antigens carriers of hepatitis B and living in Dakar, Senegal. We analysed the HLA-A, -B, and C antigens distribution compared to that one of a control (HBs negative) healthy senegalese population (n = 96) living in Dielmo village where a longitudinal study was set-up since 1990. The HLA class I typing was performed by microlymphocytotoxicity assays. The most frequent HLA-A, -B, -C antigens found were: locus A: A23 (33.6%), A2 (25%), A30 (25%), locus B: B8 (31%), B7 (16.3%), B58 (11.9%), B35 (11%), B49 (11%), B53 (10.8%) and locus C: Cw7 (39.1%), Cw17 (39.1%), Cw3 (36.9%), Cw4 (36.6%). Significant differences (P < 0.001) were found between the donors and the control group for the following HLA antigens: A1, A23, B8 and Cw3. The detection of HBe antigen was positive in 26/84 blood donors. It was observed a significant difference (p < 0.01) between positive and negative HBe donors for HLA-A1 allele with an odds ratio of 6.25. All the donors carrying the HLA haplotype: A1-B8-Cw7 (11.5%) were positive in HBe antigen. HLA: B8-Cw7 haplotype (detected in 8.5% of positive donors) seems to be likely associated with a liver cancer according to many reports. An adequate follow-up should be set-up for positive HBe subjects carrying a susceptible HLA type.