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Le neuroblastome (NB) est une tumeur pédiatrique maligne du système nerveux périphérique, caractérisée par une grande hétérogénéité clinique, évolutive et génétique, le plus souvent sporadique. De rares formes familiales sont décrites, compatibles avec une transmission dominante. Par ailleurs, des tumeurs neuroblastiques sont observées chez des patients porteurs d’autres anomalies de la crête neurale, comme la maladie de Hirschprung, le syndrome d’Ondine. Nous avons identifié le gène PHOX2B comme premier gène de prédisposition au NB. En effet, des mutations constitutionnelles de ce gène ont été caractérisées dans des formes familiales de NB ainsi que chez des patients présentant une association NB/maladie de Hirschsprung. Récemment, notre groupe et d’autres équipes ont identifié le gène ALK, (Anaplastic Lymphoma Kinase), comme gène de prédisposition au NB. Ce gène code pour un récepteur transmembranaire à activité tyrosine kinase. Des mutations somatiques du gène ALK ont par ailleurs été caractérisées dans des tumeurs sporadiques. L’identification de mutations constitutionnelles des gènes PHOX2B et ALK va permettre d’améliorer la prise en charge des familles à risque en proposant une surveillance adaptée aux enfants porteurs d’une mutation. [ABSTRACT FROM AUTHOR]

Background: Birt-Hogg-Dubé syndrome (BHDS) is an autosomal-dominantly inherited genodermatosis that predisposes to the development of benign hair follicle tumours, lung cysts, kidney tumours, and possibly colonic cancers, due to mutations in the FLCN gene. We report cases involving a new mutation in three unrelated families., Materials and Methods: Blood samples of three probands were submitted for a molecular diagnosis of BHDS. Following DNA extraction, FLCN gene sequencing was performed. The identified mutations were confirmed on a second sample. A cancer genetics consultation was organized and specific tests (dermatological examination, CT scan of chest and abdomen and colonoscopy) were proposed for each BHDS patient., Results: FLCN gene-sequencing analysis revealed an identical complex harmful mutation in all three families. The first proband showed fibrofolliculomas (FF), a history of pneumothorax and colonic adenoma. The mutation was found in a brother and two sisters, who were asymptomatic, and in a niece with FF. The second proband showed FF. The mutation was found in her mother, who had FF. The third proband presented diffuse emphysema and very rare FF., Discussion: This case report shows extremely wide intra- and interfamilial phenotype variation within individuals having a similar FLCN gene mutation. In large cohorts of BHDS patients, no genotype-phenotype correlation has been shown. This case emphasises the vital importance of presymptomatic diagnosis for each member of a BHDS family by means of a cancer genetics consultation, followed by a CT scan of the chest and abdomen, colonoscopy and annual kidney imaging., (Copyright 2010. Published by Elsevier Masson SAS.)

We report two cases of familial juvenile polyposis coli. SMAD4 gene mutation was found in our two patients, leading to the definite diagnosis. Colonic cancer occurred in the first patient. Long-term outcome was favorable after colectomy. In the second patient, prophylactic total colectomy was performed. Rectal bleeding, diarrhea, stomach obstruction and vomiting developed during the follow-up. Proctectomy, distal partial gastrectomy and total gastrectomy were successively performed.

The Li-Fraumeni syndrome (LFS) is an inherited form of cancer, affecting children and young adults, and characterized by a wide spectrum of tumors, including soft-tissue and bone sarcomas, brain tumours, adenocortical tumours and premenopausal breast cancers. In most of the families, LFS results from germline mutations of the tumor suppressor TP53 gene encoding a transcriptional factor able to regulate cell cycle and apoptosis when DNA damage occurs. Recently, germline mutations of hCHK2 encoding a kinase, regulating cell cycle via Cdc25C and TP53, were identified in affected families. The LFS working group recommendations are the following: (i) positive testing (screening for a germline TP53 mutation in a patient with a tumor) can be offered both to children and adults in the context of genetic counseling associated to psychological support, to confirm the diagnosis of LFS on a molecular basis. This will allow to offer to the patient a regular clinical review in order to avoid a delay to the diagnosis of another tumor; (ii) the 3 indications for positive testing are: a proband with a tumor belonging to the narrow LFS spectrum and developed before age 36 and, at least, first- or second-degree relative with a LFS spectrum tumor, before age 46, or a patient with multiple primary tumors, 2 of which belonging to the narrow LFS spectrum, the first being developed before 36 or a child with an adenocortical tumour; (iii) presymptomatic testing must be restricted to adults; (iv) the young age of onset of the LFS tumors the prognosis of some tumors, the impossibility to ensure an efficient early detection and the risk for mutation carriers to develop multiple primary tumors justify that prenatal diagnosis might be considered in affected families.

This review reports epidemiological data and biological mechanisms about the Apolipoprotein E gene allele epsilon 4 that is a major risk factor for Alzheimer's disease (AD). The second part describes the three genes, amyloid precusor protein (APP), presenilin 1 (PS1) and presenilin 2 (PS2) genes, which when mutated cause early-onset autosomal dominant AD. Mutations on each of these genes have as a common consequence elevated levels of A beta (42,3).

Germline mutations of the p53 gene are associated to the Li-Fraumeni, a rare autosomal dominant syndrome characterized by a wide spectrum of tumours including sarcomas, breast carcinomas, brain tumors and adrenocortical carcinomas. In most of the cases, tumours will develop in children and young adults. Germline p53 mutations have been identified in approximately 50% of the families with the Li-Fraumeni syndrome, and in families which only partially fulfilled the definition of the syndrome. Germline p53 mutations are mostly missense mutations, located between exon 5 and exon 8, within the DNA-binding domain of p53 and these mutations inactivate the transcriptional activity of the protein. In tumours, the wild-type allele is usually lost, which indicates, that p53 inactivation fits the Knudson model. Identification of a germline p53 mutation in an affected subject allows to establish the diagnosis of the Li-Fraumeni syndrome on a molecular basis and screening for germline p53 mutations may be performed in 1) families including two first degree relatives with cancers belonging to the Li-Fraumeni spectrum, one relative being affected before age 45, 2) children or young adults with a rare tumour of in the general population, belonging to the Li-Fraumeni spectrum, such as adrenocortical carcinoma, and 3) children or young adults under age 45 with multiple primary tumours of the Li-Fraumeni spectrum. In contrast, the clinical benefit of identifying germline p53 mutations carriers in affected families, considering the wide spectrum of tumours associated to this syndrome, remains to be established.

The Li-Fraumeni syndrome is an autosomal dominant syndrome representing a genetic predisposition to a wide spectrum of tumours including sarcomas, breast carcinomas, brain tumors and adrenocortical carcinomas. In most of the cases, tumours will develop in children and young adults. Germline mutations of the tumor suppressor gene p53 have been identified in approximately 50% of the families. In most of the cases, germline p53 mutations are missense mutations, located between exon 5 and exon 8, within the DNA-binding domain of p53. Since these mutations inactivate the transcriptional activity of the protein, they can easily be detected by analyzing in yeast the transcriptional competence of p53 cDNA derived from lymphocytes. The presence of a germline p53 mutations must be considered in: (1) families including two first degree relatives with cancers belonging to the Li-Fraumeni spectrum, one relative being affected before age 45; (2) children or young adults with a rare tumour of in the general population, belonging to the Li-Fraumeni spectrum, such as adrenocortical carcinoma; and (3) children or young adults under age 45 with multiple primary tumours of the Li-Fraumeni spectrum. Identification of a germline p53 mutation in an affected subject allows to establish the diagnosis of the Li-Fraumeni syndrome on a molecular basis.

Hyaluronic acid (hyaluronan or HA) is a major component of connective tissue synthesized by fibroblasts. Some progress has been made in recent years in the understanding of its metabolism, regulation and physiological role. The development of specific and sensitive assay methods has shown that the HA plasma level is increased in a wide variety of disorders. This increase may be due to decrease hepatic clearance, excessive synthesis (systemic sclerosis, inflammatory arthropathies, psoriasis, cancers, etc.), or even to an increased hyaluronidase activity in certain cancers. The major use of HA assays at the moment is in the evaluation of the evolutivity of those diseases where the HA increase relates to their activity. It seems to be of no diagnostic activity, at least for the time being.

Experimental studies of cell malignant transformation have shown that such transformation requires the alteration of genes that can control the expression of the transformed phenotype. In human oncology, the role of genes that suppress malignant transformation is suggested by the fact that specific genic deletions have been detected by polymorphism-detecting probes in many malignant tumours. The only oncosuppressor gene that is characterized at the moment is the inactivated RB gene in retinoblastoma. Molecular biology studies have shown that in retinoblastoma and other malignant tumours this gene is altered in its structure or expression. In addition to retinoblastoma, nephroblastoma in children and colonic carcinoma constitute models for the study of oncosuppressor genes in human oncology.