We report the case of a fifty three years old woman who has developed in the same time a breast carcinoma and a bone chondrosarcoma. The mean of this article is to underline the strong link (statistical and phenotype) between those two cancers and to discuss the possibility of a syndrome associating breast carcinoma and bone chondrosarcoma.

Malformations of cortical development are increasingly recognized as important causes of epilepsy, developmental delay and other neurological disorders. Our purpose is to present the relevance of the MRI in these pathologies with the clinical, genetic and therapeutic aspects. This classification is based on the three fundamental events of cortical formation: proliferation of neurons and glie in the periventricular zone, migration of postmitotic neurons to the periphery, subsequent cortical organization. MR analysis evaluates particularly the cortical thickness, sulcal and cortical morphology, gray-white matter junction, and looks for gray matter in abnormal location. These data coupled with the familial history, the seizure characteristics and genetic findings should allow an appropriate classification of the lesions. MR imaging allows the detection and classification of cortical malformations. MR imaging findings are primordial to consider surgery when the epilepsy becomes refractory to the anti-epileptic drugs. An adequate classification of these malformations should help to provide to the family an appropriate counseling both in terms of genetics and outcome.

Some diffuse type gastric cancers are of hereditary origin. Their histological characteristics are poor cell differentiation and the presence of signet-ring cells. The cause is a mutation of the CDH1 gene which is responsible for abnormal E-cadherin. The transmission mode is autosomal dominant. Because of serious prognosis of symptomatic hereditary diffuse gastric cancer (HDGC), the high penetrance of the gene (67% in men and 83% in women) and the young age of onset of these tumors (before the age of 40), a prophylactic gastrectomy is recommended to the mutation carriers. The search for the genetic mutation should be recommended to families corresponding to clinical criteria such as the number of affected family members, degree of relationship and age of onset of these tumors.

Colonic mucus is a key element of colonic barrier as it is located at the frontier between luminal microflora and colonic mucosa itself. Colonic mucus is mainly composed of high molecular weight glycoproteins called mucins that can be either secreted or membrane-linked. The expression of various colonic mucins is altered in colorectal cancers or inflammations. The aim of this review is to highlight the crucial role played by colonic mucins in the maintenance of colonic barrier integrity, both because they are part of the protective mucus layer, and because they individually exert specific functions involved in epithelial barrier, like cell growth and differentiation, immunomodulation, signal transduction or cell adhesion.

Cutaneous melanoma is a complex disease involving genetic and environmental factors. Levodopa has been incriminated in the development and/or progression of melanoma.

We report two cases of Bazex-Dupré-Christol syndrome in a father and daughter with divergent clinical pictures at two different ages.

A complete blood analysis with a careful morphologic examination of peripheral blood and bone morrow smears completed by cytochemical reaction will help to classify the most acute myeloid leukaemia (AML). Actually, the study of other cytogenetis and immunophenotypic markers are now necessary to confirm diagnosis. The World Health Organisation WHO classification (2001) incorporates theses approaches. The purpose of this study is a bio-clinical review according to the WHO recommendations in 153 cases of LAM diagnosed between January 1998 and December 2003. The patients were aged 2 months to 90 years with sex ratio (M/F) of 1,22. The morphologic conclusion was difficult in 12% cases. Presence of dysplasia is noted in 50% of cases with multilineage dysplasia in 42% of cases. Our results showed cloned chromosomal abnormalities in 57% of cases (t(8;21): 12%, t(15;17) : 10%, Inv16: 1,3%, 11q23: 2,6% et complex karyotype: 14,3%). In 69% of cases with multilineage dysplasia, the karyotype was normal. 3 cases of LAM were noted at patients treated for breast cancer with chirurgic chemotherapy and radiotherapy 3, 4 et 5 years after treatment (LAM3 with t(15;17), LAM4 with genetic abnormalities of chromosomes 3, 5, 7, 8, 9, 14 et 16 et LAM 6 with genetic abnormalities of chromosomes 4, 7, 12, 14, 19 et 21). In WHO classification, cytology is essential in diagnosis of LAM even if the karytype have an important prognostic value. Research of signs of dysplasia lineage after lineage constitutes an important microscopic work and it is difficult to quantify dysplasia when the lineage is poor.

Although a rare entity, multiple gliomas must be recognized and distinguished from other causes of multiple brain lesions.

The transcriptional regulation of p16INK4a is essential for cellular aging and oncogenic stress response. This regulation involves p16INK4a transcriptional activators such as proteins Ets1 and 2 or E47. The binding of these proteins to INK4a promoter can be inhibited by proteins Id-1 or -4 after heterodimer formation. The transcriptional inhibition of p16INK4a includes also the transcriptional repression by Bmi-1, and an epigenetic regulation which appears complex and remains incompletely understood. Actually, INK4a promoter and exon1 present a CpG island which can be methylated on cytosines by DNA methyltransferases. This DNA methylation is preceded by the lysine 9 histone H3 methylation and by the deacetylation of histone H4 both involved in gene silencing. Indeed, RNA Helicase A might protect INK4a against methylation of CpG island. Furthermore, chromatin remodelling involving SWI/SNF complex, antagonist to Bmi-1, might activate INK4a expression. The analysis of INK4a regulation mechanisms and the comprehension of the epigenetic modulation of its expression may allow us to develop a rational use of new anti-neoplastic agents.

Vascular anomalies, divided into vascular tumors and vascular malformations, are localized defects of angiogenesis. Hemangiomas appear soon after birth, grow quickly, and then spontaneously, but slowly, disappear. In contrast, vascular malformations are congenital defects of vascular development that grow proportionately with the child. Most vascular anomalies are considered non-hereditary. However, due to detailed analysis inherited forms have been observed, which has led to identify mutations in three genes causing familial vascular malformations: in the angiopoietin receptor TIE2 in mucocutaneous venous malformations (VMCM), in glomulin in glomuvenous malformations (GVM) and in RASA1 in the newly recognized phenotype capillary malformation-arteriovenous malformation (CM-AVM). Identification of the causative genes has permitted more precise diagnosis and differential diagnosis, evaluation of phenotypic variability among patients with a proven mutation, study of used treatments in more homogeneous patient groups, and elucidation of the etiopathogenic mechanisms behind vascular malformations. Further studies are needed to unravel the role of genetic variations in the various vascular malformations and to unravel the precise molecular mechanisms that lead to development of these vascular lesions. This should provide development of new-targeted therapies.

For most of the 25,000 human genes, the removal of introns by pre-messenger RNA splicing represents an essential step towards the production of functional messenger RNAs. Moreover, a majority of pre-messenger RNAs is alternatively spliced to yield different messenger RNAs. Cancer cells often display aberrant profiles of alternative splicing producing isoforms that can stimulate cell proliferation and migration or improve resistance to apoptosis. While mutations at splice sites or in splicing control elements have been identified, changes are also caused by alterations in the expression of proteins that affect splice site selection. Current challenges consist in documenting the functional diversity generated by alternative splicing and its contribution to different types of cancers. The development of innovative approaches aimed at reprogramming alternative splicing offers promising perspectives in cancer therapy.

Estradiol is a potent growth factor of breast cancer cells and inhibition of its activity has been a basis for the treatment of this disease for a long time. Estradiol exerts its action mainly through a nuclear receptor (ERalpha) that recognizes specific sites in the genome and regulates the transcription of neighboring genes. The identification of the repertoire of estrogen responsive genes is considered an essential step for our comprehension of the biological functions of the hormone and of the molecular mechanisms by which ERalpha control gene expression. The technology combining immunoprecipitation of DNA fragments and hybridization to DNA chips currently allows the rapid identification of transcription factor binding sites on a whole-genome level. The recent utilization of this technology has not only led to the identification of numerous ERalpha target genes in breast cancer cells, but has also revealed that the receptor requires the presence of another transcription factor, known as FOXA1, to activate a specific subset of these genes. These studies have thus shown that factors like FOXA1 can be utilized to compartmentalize the action of the hormone, suggesting new opportunities to target more precisely the action of nuclear receptors for the prevention and treatment of hormone-dependent cancer.

The rising incidence of cancers affecting the kidney emphasizes the need to identify the molecular pathways involved in the initiation and progression of kidney tumors in order to counter this phenomenon. For many years, genes belonging to the PAX family have been the focus of intensive studies in the fields of organogenesis and tumorigenesis. PAX2 and PAX8 encode transcription factors essential for embryonic kidney development. Transcriptionnal repression of these factors is, however, required to allow terminal differentiation of renal epithelia. In human, maintenance and reactivation of PAX2/8 expression are frequently observed in cases of Wilm's tumor and renal cell carcinoma. The precise role of PAX2/8 in kidney cancer is still elusive but results from several studies suggest the exertion of common functions during organogenesis and tumorigenesis of the kidney. Moreover, many members of the PAX family are involved in similar cellular processes such as differentiation/proliferation, motility and apoptosis. Thus, by comparing the functions exerted by PAX factors in several types of cancers should be useful to better define the specific contribution of PAX2/8 to kidney tumorigenesis.

Pediatric cancers affect approximately 1 in every 500 children before the age of 15. Little is known about the etiology of this heterogeneous group of diseases despite the fact they constitute the major cause of death by disease among this population. Because of its relatively high prevalence, most of the work done in pediatric oncogenetics has been focused on leukemias, particularly acute lymphoblastic leukemia (ALL). Although it is now well accepted that genetic variations play a significant role in determining individual's cancer susceptibility, few studies have explored genetic susceptibility to childhood leukemia with respect to common polymorphisms. The biochemical and genetic mechanisms contributing to cancer susceptibility are numerous and can be grouped into broad categories: 1) cellular growth and differentiation, 2) DNA replication and repair, 3) metabolism of carcinogens, 4) apoptosis, 5) oxidative stress response and 6) cell cycle. To evaluate whether candidate genes in these pathways are involved in childhood leukemogenesis, we conducted association studies. We showed that leukemogenesis in children may be associated with DNA variants in some of these genes and that the combination of genotypes seems to be more predictive of risk then either of them independently. We also observed that, at least at some loci, the parental genetics might be important in predicting the risk of cancer in this pediatric model of a complex disease. Taken together, these results indicate that the investigation of a single enzyme and/or a single genotype might not be sufficient to explain the etiology of childhood leukemia because of the complexity of the environment and that of the inter-individual variability in cancer susceptibility.

The unique genetic demography of the French Canadian population of Quebec, Canada, has provided a means to study the contribution of BRCA1 and BRCA2, the breast-ovarian cancer susceptibility genes. Here we review BRCA1 and BRCA2 in the context of French Canadian cancer families, a well-characterized founder population known for its contributions to medical genetics. Pathogenic BRCA1 and BRCA2 mutations contribute to a significant proportion of hereditary breast and/or ovarian cancer families of French Canadian descent. BRCA1 and BRCA2 mutations have been reported in approximately 40 % of families with at least three cases of breast and/or ovarian cancer, where breast cancer diagnosis occurred before age 66 years, and where all cases occurred within first-, second- and/or third-degree relatives to index affected cases tested for mutations. The proportion of mutation-positive families was very similar to that reported in independent studies of families not selected for ethnicity. However, 84 % of mutation-positive families were accounted for by one of eight pathogenic mutations in BRCA1 (2953delGTA + C, 3875delGTCT, and 4446C --> T) and BRCA2 (2816insA, 3398delAAAAG, 6085G --> T, 6503delTT, and 8765delAG). Haplotype analyses has suggested that carriers of the most common recurring mutations share a related ancestry. This effect has been attributed to common founders in the French Canadian population of Quebec who emigrated from France in between 1608 and 1759. It is possible that novel highly penetrant cancer susceptibility genes account for a fraction of the 60 % of BRCA mutation-negative French Canadian cancer families. The continued genetic analysis and phenotypic characterization of French Canadian cancer families is warranted given the large family structure of these families are amenable for classical genome-wide linkage analysis for novel breast and ovarian cancer susceptibility genes.

Molecular anomalies of the Y chromosome leading to male infertility are mainly microdeletions of the long arm of the Y chromosome. Three recurrently deleted portions of the long arm are the AZFa, AZFb and AZFc (AZF: Azoospermia Factor) regions. Complete deletions of the AZFc region are found in 10% of cases of severe male infertility. In addition to the AZF deletions, certain classes of Y chromosome (haplogroups) may also predispose to male infertility and could be transmitted to future male descents by various Assisted Reproductive Techniques (ART). Since the first discovery of microdeletions, the sequence of the Y chromosome has become available, revealing the mechanisms underlying deletion formation and also resulting in a coherent screening strategy. Recently, partial deletions of the AZF regions have been described. The significance of these deletions in the clinical context remains to be defined.

The term "targeted therapies" designs treatments directed towards molecular targets present on or within tumor cells, and contributing to the process of malignant transformation. These can be categorized in several different groups: 1) Targeted therapies directed against molecular targets which play the initial and critical role in neoplastic transformation; these treatment generally yield high response rates as single agent treatment. 2) Targeted therapies on late molecular targets contributing to tumor progression, but which do not correspond to the initial event; these treatments provide limited response rates as single agent but most often improve progression free and/or overall survival in combination with cytotoxic treatments. When the molecular target is present in tumor cells, but does not contribute to neoplastic transformation, these agents are generally non active in an in vivo setting. These observations point out the need to introduce translational research as a key element to schedule and evaluate the activity of novel targeted agents in the clinics.