Since its discovery, the CDKN2/MTS1 locus has been considered as an important site for the understanding of cell cycle deregulations that are involved in cancer cell generation. A comprehensive approach of the respective roles played by the two p16INK4a and p14/p19ARF (ARF) proteins encoded by this locus was not yet achieved because of the structural intrication of their genes. Inactivation of the only p16INK4a gene in mouse allowed to get better insight into this puzzle. In vivo results presented by de Pinho's group showed that inactivation of both p16INK4a alleles generated a panel of various types of tumors from the 28th week following birth. Bern's group dit not confirm this result but showed that the presence of only one ARF functional copy increases sensitivity of p16-/- mice to tumor occurrence indicating that insufficient dosage of ARF protein may facilitate tumorigenesis. It seems now established that, at least in mouse, ARF controls senescence in vitro, immortalisation and transformation by oncogenic ras. p16INK4a inactivation appears to be crucial for the induction of carcinogens-induced tumors.

The retinal pigment epithelium (RPE) develops from the same sheet of neuroepithelium as the neuroretina. When infected with MC29, a v-myc expressing virus, the RPE cells can be induced to transdifferentiate and to take a neuroretinal epithelium fate. After a PCR-based differential screening from these cells we have identified three genes of interest. Qath5, a quail basic helix-loop-helix (bHLH) gene that is closely related to the Drosophila atonal, and whose expression is found in the developing neuroretina. A Chx10-related homeobox gene also expressed in the developing neuroretina and HuD, a RNA-binding protein not expressed in the RPE but expressed during neurogenesis. Beside these genes whose function is involved in regulating neuronal differentiation myc also induced a transient Mitf expression. Mitf is expressed in the entire optic cup, later restricted to the pigmented retina. Mitf is involved in the regulation of the pigmented differentiation. We conclude that v-myc can reverse the RPE to the bipotential retinal primordia.

Cytogenetic analyses have revealed that mantle cell lymphomas (MCL) are closely associated with the t(11;14)(q13;q32). This translocation juxtaposes the immunoglobulin heavy chain gene (IGH) sequences with the BCL-1 locus, leading to up-regulation of the CCND1 gene and consequently to an overexpression of cyclin D1 protein. We studied 27 MCL with characteristic morphological and immunological (CD5+, CD10-, CD20+, CD23-) features and 2 controls (reactionnal lymphadenitis) to evaluate the feasibility and the interest of FISH analysis on interphase cells from frozen or paraffin-embedded tissues. Sections (CC) and touch preparations (EC) of frozen tissues and sections of paraffin-embedded tissues (CF) were successfully hybridized with the Vysis LSI IgH/CCND1 dual color dual fusion translocation probe. The touch preparations presented a lower cellularity than sections, therefore allowing an easier analysis. Hybridization spots intensities were found stronger in CC and EC than in CF. The percentages of t(11;14) positive cells were similar in CC, EC and CF from a same patient. The percentage of non hybridized cells, analogous in CC and EC, was higher in CF. However, the CF were directly analysed on microscope without the need of any numerical picture treatment. The t(11;14) was detected in all the cases (27/27) and positive cells percentages were always higher than the probe cut-off (5%). The FISH analysis on interphase cells appears a performing and rapid technique to detect t(11;14) in MCL on both frozen and paraffin-embedded tissue, thus extending its practical and diagnostic use.

Microarray technology has recently led to the identification of molecular prognostic subgroups in non Hodgkin's lymphomas. In order to determine the usefulness of ready-made macroarrays as routine diagnosis tools in haemato-pathology, we have analysed lymph node biopsies using a cDNA macroarray containing genes involved in apoptosis, including caspases. Nine biopsy specimens were analysed on total frozen tissues: 4 samples of B-cell follicular lymphoma (FL), two of B-cell diffuse large cell lymphoma (DLCL), and three of non-neoplastic lymph nodes from benign lymphadenitis. Eight cell populations were sorted from fresh tissues: malignant B-cells from 2 FL cases and 2 DLCL cases, reactive B-cells from 1 benign lymph nodes, reactive T-cells from 1 benign lymph node, virgin (mantle zone) B-cells and germinal center (GC) B-cells from benign tonsils. Immunohistochemistry (IHC) on paraffin sections was performed for localization of caspases 2, 3, 4, 7, 8, and 9. In the clustered array data, sorted cells from samples sharing common histological lesions grouped together, whereas the array/histology correlation was less satisfactory for tissues. The expression profiles of both array and IHC methods were correlated for most caspases and samples. Variations in array profiles of sorted cell populations can be statistically associated with specific histological features, suggesting a possible diagnostic application of ready-made "Apoptosis macroarrays" in haematopathology.

In most tumor cells a chromosomal instability leads to an abnormal chromosome number (aneuploidy). The mitotic checkpoint is essential for ensuring accurate chromosome segregation by allowing mitotic delay in response to a spindle defect. This checkpoint delays the onset of anaphase until all the chromosomes are correctly aligned on the mitotic spindle. When unattached kinetochores are present, the metaphase/anaphase transition is not allowed and the time available for chromosome-microtubule capture increases. Genes required for this delay were first identified in Saccharomyces cerevisiae (the MAD, BUB and MPS1 genes) and subsequently, homologs have been identified in higher eucaryotes showing that the spindle checkpoint pathway is highly conserved. The checkpoint functions by preventing an ubiquitin ligase called the anaphase-promoting complex/cyclosome (APC) from ubiquitinylating proteins whose destruction is required for anaphase onset.

Spindle cell lipomas are rare adipose tissues tumors. Histologically, these lesions are composed of mature adipocytes and spindle cells associated with collagen bundles. Spindle cell lipomas are benign tumors that can be difficult to distinguish from malignant tumors such as spindle cell liposarcomas, myxoid liposarcomas or well-differentiated liposarcomas.

Currently, more than 4,000 newly colorectal cancer are diagnosed each year in Belgium. The individual average-risk for developing colorectal cancer is about 5%. 90% of colorectal cancer occurred after the age of 50, and in 70% of the cases in patients without particular risk factors (average-risk population). Personal and/or familial history of colorectal adenoma, colorectal cancer, inflammatory bowel disease localised to the colon, familial polyposis syndrome or Hereditary Non Polyposis Colorectal Cancer (HNPCC) increase the risk of colorectal cancer. An individual appropriate screening of high-risk patients and average-risk asymptomatic patients older than 50, together with endoscopic resection of adenoma decrease the incidence and the mortality of colorectal cancer. Usual screening methods are fecal occult blood testing which is not proven to be efficient alone for individual screening (but still recommended for general population's screening), sigmoidoscopy (which has to be completed by a colonoscopy, if lesions founded), and colonoscopy. Virtual colonoscopy and genetic testing need further evaluation. Currently, colonoscopy seems to be the goldstandard method providing complete examination of the whole colon and being the most cost-effective method. Screening strategy should be decided on an individual basis considering the patient's benefit with respect to the informed consent.

Cancer is a hereditary disease at the level of an individual cell and its daughter cells. The tumor genotype causing the tumor phenotype is now quite well known in colorectal cancer and allows, among others, to perform pathology examination at the molecular level. A distinct topic addresses individual predisposition to colorectal cancer. Its molecular nature is well know in the relatively rare cases, about 5-10% of colorectal cancers, where such a predisposition is major, and is transmitted in families of affected subjects following a hereditary, mendelian mode of inheritance. Specifically, two types of hereditary adenomatous tumors, polyposis and hereditary nonpolyposis colorectal cancer, may benefit from genetic analysis in order to target cancer prevention. New genetic tests will probably develop in the coming years, allowing for the analysis of more modest, and less clearly hereditary individual risks.

In some circumstances and despite investigations, no aetiology is found for hypereosinophilia. This becomes of particular concern when hypereosinophilia is elevated and persistent. While some chronic hypereosinophilias signal the onset of malignant haemopathies, others remain unexplained for up to several years. But all may cause severe complications to the viscera, among which cardiopathies, and in particular endomyocardial fibrosis, are predominant. New data on chronic unexplained hypereosinophilia point to regulation defects in eosinophils or more often in T lymphocytes. Thanks to simple investigations such as flow cytometry, along with other more sophisticated procedures, we should soon be better equipped to classify chronic hypereosinophilia and, in the long term, to define more adequate strategies for treatment.

Currently it is evident that human papillomaviruses are involved in the development of cervical cancer. The mechanisms of cancer initiation are in relation with certain types of papillomavirus. But the discrepancy between the high prevalence of papillomavirus infection and the low frequency of cancer in infected women, gives evidence of the importance of healing process in relation with the host's immune response and the activation of other carcinogenic factors. The understanding of the role of papillomavirus in cervical cancer, gives prospects to prophylactic and therapeutic strategies in relation with antiviral treatments or papillomavirus-specific vaccines.

Chronic myeloid leukemia is a myeloproliferative disorder clinically characterised by a triphasic course: after a chronic phase over a median time of 4 years, patients developed an accelerated phase, then a blastic phase, resulting in the patient's death with 3 to 6 months.

About 5% of colon cancer cases correspond to classic hereditary monogenic mendelian transmission involving at least 8 major genes of predisposition to this tumor. Genes with more moderate effects, in association with other genes can contribute to the occurrence of sporadic polygenic forms. These genes confer susceptibility to environmental factors and can play the role of aggravating or protective modifier genes in the different hereditary forms. Foods can interact with these genes and modulate their expression. Moreover sequence variations (polymorphisms) in these genes may also be responsible for slower or more rapid metabolism of nutrients leading to toxic or carcinogenic compounds. If some foods, or "pharmafoods" can have beneficial effects in some individuals with a particular subtype of the disease, others can be inefficient or even detrimental in patients with the same disease but with a different genetic origin or if the genetic background is different. Moreover tumorigenic processes are diverse. Tumor progression depends on genetic and environmental factors different from tumor initiation and on the site of the tumor along the colon tract. Interactions with the gut flora, the lymphoid system and specific features of growth of the colon mucosa are also important parameters. Today with a formidable genetic knowledge arising from the genome project, new epidemiological data integrating the genetic data for multiple markers and a better knowledge of the tumorigenic processes involved, a new discipline is emerging. "Nutrigenetics" which is the study of hereditary basis of individual variations in response to foods opens for the oncoming decade the era of a personalised predictive medecine based on a nutrition adapted to the genetic make up of each of us.

Thanks to progress in molecular genetics, we now have new powerful tools allowing certain or highly presumptive prediction of disease course. The impact on medical practice has been disconcerting. These tools may be very helpful for many patients and families concerned by genetic diseases. For health professionals, the new knowledge must be handled with care to discern the true patient benefit. The patient-doctor relationship - from information delivery, with its known or unknown effects on the individual patient and his/her family and offspring, to the new prospects for gene therapy - must be conducted in a spirit of free exchange allowing responsible real life decision making. Living necessarily implies taking risks, but also trusting human capacity to establish mutual relationships on the basis of trust, fellowship and fraternity.

A few definitions Exploration methods (unknown mutations) Diagnostic methods (known mutations) New technologies and perspectives What should be done when no mutation can be identified? Research strategies in oncogenitics

Pathologists have long been in charge of the morphological analysis of human cancers, and have been used to be at the end of a chain in the diagnostic procedure. With the search for somatic mutations and new prognostic markers, the pathologists have become key-members in oncogenetics. New modalities for tissue fixation, microdissection of tumors, and forwarding of specimens to the molecular biologists are therefore requested. Two examples are presented to illustrate the need for tumor DNA, with the diagnostic utility of a microsatellite testing as a prescreening test in HNPCC tumors, and the search for new prognostic markers in some inherited predispositions to breast cancers.

Hereditary non polyposis colorectal cancer (HNPCC) is characterized by an excess of early colorectal carcinomas, preferentially located on the ascending colon, associated with a variety of extracolonic cancers. The recent demonstration of germline mutations in DNA mismatch repair genes in HNPCC patients enhanced the interest due to the syndrome. Molecular genetic testing of HNPCC has become available, and should help physicians to recommend specific modalities for the surveillance and the management of patients with such a high cancer risk.