Some rare hereditary syndromes demonstrate high cancer risk and hypersensitivity in response to exposures to agents such as ultraviolet or ionising radiation, and are characterised by a defective processing of DNA damage. They highlight the importance of the individual capacity of restoring the genomic integrity in the individual risk associated to exposures. The comet assay, a simple technique that detects DNA strand breaks, requires few cells and allows examination of DNA repair capacities in established cell lines, in blood samples or biopsies. The assay has been validated on cellular systems with known repair defects such as xeroderma pigmentosum defective in nucleotide excision repair, on mutant rodent cell lines defective in DNA single strand break rejoining (XRCC1) (alkaline version) or DNA double strand breaks rejoining (XRCC5/Ku80 and XRCC7/DNAPKcs) (neutral conditions). This assay does not allow to distinguish a defective phenotype in ataxia telangiectasia cells. It shows in homozygous mouse embryo fibroblasts Brca2-/- an impaired DNA double strand break rejoining. Simplicity, rapidity and sensitivity of the alkaline comet assay allow to examine the response of lymphocytes. It has been applied to the analysis of the role of DNA repair in the pathogenesis of collagen diseases, and the involvement of individual DNA repair proficiency in the thyroid tumorigenesis induced in some patients after therapeutic irradiation at childhood has been questioned. Preliminary results of these studies suggest that this type of approach could help for adapting treatment modalities and surveillance in subgroups of patients defective in DNA repair process. It could also have some incidence in the radioprotection field.

Neurofibromatoses regroup at least two different autosomal dominant disorders, neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). NF1 gene and NF2 genes have been respectively localized on chromosomes 17 and 22. NF1 represents 95% of neurofibromatoses cases. Its incidence is 1 for 3,500 newborns, its prevalence 1 for 4,500. NF1 is characterized by its cutaneous manifestations, café au lait spots, lentigines and neurofibromas. NF2 incidence is 1 for 33,000-40,000 newborns. NF2 is characterized by bilateral vestibular schwannomas (former acoustic neurinomas) and other tumors of the central nervous system. The hallmark of schwannomatosis (neurilemmomatosis) is multiple cutaneous or subcutaneous schwannomas without vestibular schwannomas. Different neurofibromatoses are characterized by different prognosis, complications, and genetic counseling. Multidisciplinary centers with trained physicians are ideal structures for management of neurofibromatoses patients.

Von Hippel-Lindau (VHL) disease is an autosomal dominant disorder, predisposing to the development of various tumors (central nervous system and retinal hemangioblastomas, endolymphatic sac tumors, renal cell carcinoma and/or renal cysts, pheochromocytomas, pancreatic cysts and/or tumors). Incidence of the disease is 1/36,000. Central nervous system hemangioblastomas and renal cell carcinoma are the main causes of death. The VHL gene, located on chromosome 3p25-26, is a tumor-suppressor gene encoding for a 213 amino acid protein which plays a major role in regulation of VEGF expression. Germline mutations of the VHL gene are identified in about 75-80% of the patients. Somatic mutations of the VHL gene are found in both sporadic central nervous system hemangioblastomas and sporadic "clear" renal cell carcinomas. For neurosurgeons search for VHL disease should be imperative in presence of a patient with apparently "sporadic" central nervous system or endolymphatic sac tumor.

Parathyroid hormone (PTH) and PTH related peptide (PTHrP) have a common main receptor: type I PTH-PTHrP receptor. PTH expresses its main metabolic actions, and PTHrP part of its autocrine or paracrine actions through this receptor. Jansen chondrodysplasia is a very rare disease mainly characterized by severe metaphyseal growth disorders leading to dwarfism and hypercalcemia. The group of Jüppner from the Massachusetts General Hospital in Boston recently demonstrated mutations on the gene of the type I PTH-PTHrP receptor in five patients with Jansen chondrodysplasia. These mutations result in permanent activation of the receptor responsible for the observed hypercalcemia and bone growth abnormalities due to the disease. Therefore Jansen chondrodysplasia appears as a remarkable clinical model outlining the major role of PTHrP in bone growth regulation.

The different types of activating mutations of LH and FSH receptors genes are described. They result in a constitutive permanent activation of the LH or FSH function responsible for functional disorders which is also observed in some ovarian tumours. Two types of functional disorders have been reported: male precocious puberty through activating mutation of the LH receptor, male fertility in the absence of FSH through activating mutation of the FSH receptor. Activating mutations of the FSH receptor observed in certain ovarian tumours result in hypersecretion of oestrogens.

Mutations of the TSH receptor gene cause constitutive activation of the TSH receptor responsible for cases of familial hereditary hyperthyroidism (germline mutations), cases of sporadic congenital hyperthyroidism (de novo mutations), and thyroid hyperfunctioning autonomous adenomas (somatic mutations). The discovery of these mutations not only clarifies the pathogenesis of some forms of thyroid autonomy, such as cases of persistent neonatal hyperthyroidism without maternal thyroid autoimmunity, but also contributes to a better understanding of the structure-function relationships of the TSH receptor.

Follicular lymphoma constitutes 30-40% of non-Hodgkin's lymphomas. Most patients have widespread disease at diagnosis. The clinical course is generally indolent, and it is not usually curable with available treatment. The source of relapse in patients who achieve complete clinical remission is residual neoplastic cells that are present below the limits of detection using standard techniques. With the development of PCR technology, the presence of these residual malignant cells [Minimal Residual Disease (MRD)] has been demonstrated clearly. Recently, an association of high-dose chemotherapy with autologous bone marrow or peripheral blood progenitor cell autograft appeared promising in the treatment of these lymphomas. In the search of clonal markers for the detection of MRD in follicular lymphomas, two strategies can be used. In the cases associated with the t(14;18) (q32;q21) chromosomal translocation, the bcl-2/JH junctional regions are amplified by PCR in approximately equal to 50% of cases and then sequenced in order to synthesize an anti-junction oligonucleotide probe specific for each patient's malignant clone (clonospecific probe). In the cases negative for this translocation, an alternative strategy consists in the amplification of immunoglobulin high chain (IgH) gene rearrangement (approximately equal to 75% of cases). The present review highlights the value of molecular markers such as bcl-2/JH and VH/JH rearrangements to follow the neoplastic clone and to detect MRD in patients with follicular lymphomas.

The hepatitis B virus belongs to the hepadna viruses family. Its genome consists of an incompletely double stranded DNA. The preS/S domain encodes proteins which make up the outer viral coat containing the HBs surface antigen (HBsAg). Other viral genes programme for structures inside the virus and for various regulatory enzymes. HBV mainly infects hepatocytes. The virus replicates in the cytoplasm and is primarily non-cytopathogenic. HBV can also integrate into the host cell. Various stable genotypes and subtypes are known, which have a characteristic geographic distribution. They all share a common HBsAg epitop, which has allowed the development of a vaccine which is efficient world-wide. The protective principle consists of inducing protective anti-HBs. The infected cell has to be destroyed to eliminate the virus. Cellular immune defence mechanisms are mainly relevant, the principle effectors being cytotoxic T lymphocytes, activated monocytes/macrophages and cytokines such as interferon-gamma. The natural course of infection is highly variable, comprising viral elimination with or without acute hepatitis and chronic infection which might lead to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. This is due to the balance respectively to the inbalance between the viral replication capacity and the immune defence mechanisms.