Ten percent of all cavernomas are familial forms. 300 independent families have been identified in France since 1995. Clinical manifestations are more frequent in familial (50%) than in sporadic forms (5%). The symptoms are the same in both forms: epilepsy, hemorrhages, neurological focal deficits and headache, but hemorrhages are more frequent and the age of revelation is younger, before 30 years. It is also frequent to observe extraneural location, cutaneous and retinal. On MRI, four types of lesional aspects were described and lesions are multiple in all cases with numerous "de novo" cavernomas. The prognostic does not depend on the number of lesions, but on their topography, especially in the brain stem. Familial forms may be considered not only as a neurological but as a systemic disease for which global management with a genetic counseling should be considered. Gene therapy is not today available, but perhaps in the future.

Confluent and reticulate papillomatosis of Gougerot and Carteaud is a rare entity and a subject of controversy in terms of nosology. It has occasionally been regarded as a peculiar variant of acanthosis nigricans, pityriasis versicolor or amyloidosis.

Therapies targeted on cell signal pathways that control cell division and tumor angiogenesis have been developed over the last five years for non small cell lung cancer (NSCLC) with some amazing results, in subgroups of selected patients, predicting more significant success in the upcoming years. Compounds targeted on EGF tyrosine kinase receptor have been tested in large clinical phase 2 and 3 trials including thousands of patients. Their efficacy has been proved, in second and third line trials, after first line cisplatin-based chemotherapy for non-mucinous adenocarcinoma in non-smokers, women and Asian patients. Response rates vary from 10% in non selected Caucasian patients to 40% in non-smoking Asian patients with long survivals. Therapeutic targeting improves success rates, either relying on EGFR gene amplification detection by FISH, or search for EGFR tyrosine kinase domain mutations. Commercial kits are available for routine molecular diagnosis of domain mutations potentially enabling molecular targeting in addition to clinical targeting. Angiogenesis inhibitors, especially monoclonal antibody to VEGF, bevacizumab, have also been developed in the last few years. Bevacizumab associated with classical cytotoxic chemotherapy led, in selected patients (with non squamous cell lung cancer and no past history of cardiovascular disease) to an increase of median survival to more than 12 months with tolerable toxicity. Other drugs that have both anti-EGFR activity and anti-angiogenic properties will be soon developed, since future bioactive anti-cancer drugs will probably be multi-targeted drugs.

Aneugenic compounds cause chromosome missegregation during cell division and induce aneuploidy in cells that do not die. Aneuploidy is a key step in the progression from a normal cell into a cancerous cell, and it could represent an early event in the carcinogenic process. Missegregation of chromosome during anaphase often originates from centrosome abnormality, which plays a key role in the formation of the mitotic spindle during cell division. Micronuclei (MN) are thought to be biomarkers of chromosome damage due to genetic instability or exposure to environmental mutagens or carcinogens (occupational exposure for example). The MN assay in combination with fluorescent in situ hybridization discriminates between MN containing acentric chromosome fragments (chromosome breakage) and MN containing whole chromosomes (chromosome loss), consecutively to clastogenic and aneugenic events, respectively. Centromere-positive micronuclei are due to alteration in mitotic apparatus proteins. Two pathways could be involved : chromosome migration impairment would lead to MN containing a single chromosome whereas centrosome amplification would induce MN containing several chromosomes. For biomonitoring purposes, numerous confounding factors (host factors, lifestyle, genetic polymorphism) influence the MN biomarker. Thus, the separated analysis of MN containing a single or several centromeres could be useful, as centrosome abnormalities seem to be linked with an increase in genetic instability.

The relation between circadian physiology (rest-activity and body temperature) and the growth of a grafted tumor (Glasgow osteosarcoma-GOS) was investigated in the mice with mutation of clock gene (ClockDelta19(-)) or gene controlled by the clock (Vpac(-/-)). Circadian rhythms in temperature and activity were stable, with an approximately 24-h period in all the mice synchronized by the alternation of 12 h of light and 12 h of darkness (LD 12:12). Following exposure to constant darkness (DD), both rhythms persisted in ClockDelta19(-), yet with a lengthening of the period by 4.5 h compared to wild type. In DD, the amplitude increased by 45.9% for the temperature rhythm (p<0.001) and by 17.4% for the activity one (p=0.08) as compared to LD 12:12 in ClockDelta19(-). The improvement of circadian coordination and/or the lengthening of the circadian period observed in ClockDelta19(-) kept in DD was associated with a moderate slowing down of tumor growth. Although the exposure to DD ablated the activity and temperature rhythms in Vpac(-/-), no modification in tumor growth was observed as compared to wide type or Vpac(-/-) in LD 12:12. Major alternations of circadian physiology can result from interactions between photoperiodic environment and mutation of clock gene or gene controlled by the clock. In these conditions, we have shown that the alternation of the circadian phenotype does not seem to constitute an essential determinant of the growth of a grafted tumor.

The authors reviewed experimental and clinical data emphasizing the importance for host to keep a reference circadian rythmicity. This assessment seems true both in the cancerogenesis phase, as well in the active phase of tumoural disease.

Since the early 80's, cancer research has been dominated by scientific breakthroughs demonstrating the genetic origin of cancer. Thousands of genetic alterations have been identified, affecting more than one hundred cell regulating genes. In the past ten years, our understanding of carcinogenesis has evolved: cancer is both a genetic and an epigenetic disease. Epigenetic modifications play a fundamental biological role in the initiation and progression of cancer by altering the expression of cell cycle regulation genes. Unlike genetic mutations, epigenetic modifications are potentially reversible. Thus, epigenetic inhibitors are currently evaluated as anticancer drugs. Moreover, DNA methylation study holds promise as biological marker for classification, diagnostic and prognostic purposes in clinical practice.

Wermer's syndrome or Multiple Endocrine Neoplasia Type-1 (MEN1) is an autosomal dominant inherited disease, related to mutations in MEN1, an approximately 10-kb gene encoding menin, localized on chromosome 11q13. The Endocrine Tumor Group (GTE) has set up a MEN1 observatory of 1001 regularly followed MEN1 cases. This observatory aims at registering and evaluating MEN1 cases in a large cohort. Any new study on a particular unexplored aspect of the disease may be proposed by a physician to the GTE. This article describes the way to diagnose a new MEN1 case and to register it. Procedures for participating in a new study are presented. Some original results are quoted.

Paraganglioma are rare tumours, which develop in the paraganglionic sites of the head and the neck, and around the medulla of the adrenal gland and the sympathetic ganglions of the thoracoabdominal and pelvic regions. Their morbidity-mortality is due to the local and regional spread to the adjacent nervous and vascular structures, their hypervascularisation, the major cardiovascular complications when they are secreting tumours and the risk of recurrences and metastases. Paraganglioma can secrete catecholamines. The only curative treatment is surgical exeresis. The hereditary paraganglioma are more often multifocal, recurrent, sometimes malignant, and with an earlier occurrence than the sporadic forms. The genes responsible for the familial syndromes are the coding genes for the three sub-units of succinate dehydrogenase (SDHD, SDHB and SDHC) or mitochondrial complex II. Recent discoveries show that these genes are truly implicated in the sporadic forms of the illness and that the research for a germline mutation of a SDH gene is essential for managing patients with paraganglioma and/or pheochromocytoma and their families.

Multiple endocrine neoplasia (MEN) are major predisposition syndromes to endocrine tumours and are characterised by an autosomal dominant disorder and full penetrance. MEN-1 is a major form of hyperparathyroidism associated with a high prevalence of endocrine tumours of the pancreas, pituitary gland, adrenal cortex and the lymphoid and bronchial endocrine tissues. MEN-2 is the familial syndrome of medullary thyroid carcinoma, associated with pheochromocytoma and hyperparathyroidism. Apart from the clinical expression of their allelic variants, both syndromes are different in their physiopathogenesis, in that MEN-2 is related to the constitutional activation of the proto-oncogene RET that encodes a putative tyrosine kinase receptor, while MEN-1 is a tumour suppressor gene model, related to mutations in the menin adapter-protein of multiple intracellular functions. The study of other rarer forms of predisposition to endocrine tumours, and especially to hyperparathyroidism, has uncovered new genes such as HRPT2, which show that multiple physiological routes, including the close regulation of transcription and genetic stability, may lead to the same clinical outcome. These hereditary models of endocrine cancer contribute as much to further physiopathogenic knowledge as to the therapeutic recommendations for managing these syndromes.

Tumors arising sporadically represent 70-80% of colorectal cancer (CRC). The two best defined forms of inherited CRC-familial multiple polyposis (FMP) and Hereditary Non-Polyposis Colon Cancer (HNPCC) account respectively for<1% and 2-3% of CRC. These rare genetic syndromes (FMP, HNPCC, Peutz-Jeghers Syndrome) are caused by major predisposing gene mutations (APC gene, MMR gene, BMPR1A. SMAD4,...) and local environmental factors play only a minor role. In the sporadic forms of CRC, 25% have significant genetic predisposition probably related to alleles with weak penetration (APC*I1307K, TGFbR1*6Ala...) and are more strongly affected by environmental factors.

11beta-hydroxysteroide dehydrogenase (11beta-OHSD) enzymes exhibit a regulating action upon cortisol metabolism before access to its receptors. Two types of isoenzymes have been described, type 2 being the most anciently known. Type 2 11beta-OHSD, which changes cortisol into cortisone, is a unidirectional dehydrogenase mainly located in kidney, that protects mineralocorticoid receptors from illicit activation by glucocorticoids. Mutations of the gene coding for this enzyme has been demonstrated in apparent mineralocorticoid excess, which induces hypertension and hypokalemia with low renin and aldosterone levels. Polymorphisms of this gene could modulate essential hypertension and also be responsible for certain forms of acquired apparent mineralocorticoid excess especially after liquorice intoxication, in hypothyroidism, Cushing syndrome, and chronic renal insufficiency. Type 1 11beta-OHSD, which changes cortisone into cortisol, is a reductase, mainly located in liver and adipose tissue. Functional defects of this enzyme have been shown in polycystic ovaries and cortisone reductase deficiency. By contrast, metabolic syndrome, corticoid-induced osteoporosis, and glaucoma are linked to a local over-activity of this enzyme. The understanding of action mechanisms of these two enzymes currently leads to 11beta-OHSD inhibitors development, therefore opening new therapeutic strategies, especially in metabolic syndrome.

Does gene testing indicate a switch from an histopathological to a molecular approach of human diseases ? Disease management in oncology is already improved by gene testing, at least for some specific cancers. It is however necessary to distinguish the analysis of genes specific to the tumour which gives clues about the fate of the tumours, from those unique to the patients, which gives clues about the future of the person. For the latter so-called germline mutations, wide scale gene-default screening would put pressure on resource allocation from the health care systems of developed countries. Currently the cost of detecting of 700 genes in the whole French population would exceed the whole health budget of the country for the next 10 years. Even if we can anticipate a dramatic decrease in the unit cost of these genetic tests in the future, their diffusion should not be controlled exclusively by technological and market forces. In this paper, we propose to discuss four main parameters for regulating these genetic tests, using as an archetypal example their application to cancer prevention and treatment: (1) which specific cancer disease is targeted by the test (prevalence, incidence, likelihood of cure with current therapeutics, number of years of life potentially saved...); (2) what are the characteristics of the genes tested and which level of evidence is required about the predictive value of the test; (3) what are the size and characteristics of the population who will be offered the test, and (4) which process and public control are necessary before market approval of the test and reimbursement of related expenditures by health care insurance schemes.

More than 10 years after its initial discovery, netrin-1 - the first described chimioattractive molecule controlling the guidance of the commissural axons - has recently known a unsuspected wave of interest because of its implication in the development of the nervous system but also, more recently, fot its role in angiogenesis and tumorigenesis. Because, of a series of recent publications on netrin-1 signaling, we propose here to describe the recent insight in netrin-1 signaling via its main receptor DCC (deleted in colorectal cancer), and the recent discovery that netrin controls the assymetric distribution of beta-actin in the growth cone. Thus, it seems that netrin-1, but also the neurotrophic factor BDNF, controls acute growth cone responses such as collapse and turning by the regulation of localized protein translation, such as beta-actin. This process involves both transport of beta-actin mRNA, bound to Vg1RBP, to specific locations, and mRNA translation upon stimulation by local activation of the translation initiation regulator eIF-4E-binding protein 1. Indeed, Netrin-1 induces the movement of Vg1RBP granules into filopodia, and triggers a polarized increase in beta-actin translation on the near side of the growth cone before growth cone turning. The binding of BDNF to its receptor Trk has a similar effect for growth cone attraction, althought it is differentially regulated. Thus, this asymetrically synthesized beta-actin may direct actin polymerization and consequently the migration of the growth cone toward the cue.