Soft tissue sarcomas are rare and may be a source of problems for diagnosis and treatment. Four types of genetic disorders can be distinguished: translocations, gene amplifications, mutations and complex genetic imbalances. Detection of these disorders may help in diagnosis and in determining prognosis. Detection of specific translocation is recommended in synovial sarcoma, alveolar rhabdomyosarcoma or PNET diagnosis because of therapeutic consequences; in case of rarer histologic type (low grade fibromyxoid sarcoma, clear cell sarcoma, infantile fibrosarcoma...), it may confirm the diagnosis. In some cases, some translocations have a prognostic value (alveolar rhabdomyosarcoma) whereas it is discussed in others (synovial sarcoma). The techniques used to detect these translocations are very sensitive so it may be used to detect microscopical metastasis (bone marrow metastasis of alveolar rhabdomyosarcoma for example). Detection of MDM2 and CDK4 genes amplifications (FISH or quantitative PCR) may be sometimes useful in well differentiated and dedifferentiated liposarcomas diagnosis. Mutation detection of KIT or PDGFRA may help in GIST diagnosis and type of mutation is predictive of response to treatment. Study of complex genomic imbalances in sarcomas is not used in routine practice but remains useful in research.

Cancer is a disease resulting from complex patterns of genetic alterations that lead to malignant transformation. As such, cancer is a genetically determined disease. The vast majority of cancers are sporadic and non-heritable: genetic alterations are acquired during life, notably by exposure to genotoxic agents. However, most cancer types also have hereditary forms, reflected in extreme situations by family clusters. These forms, which represent 2 to 5% of all cancers, result from transmission of germline mutations which considerably increase the risk of cancer. Over the past fifteen years, hereditary cancers have raised much interest in the scientific and medical communities.

The conventional form of renal cell carcinoma (RCC) is a highly vascular tumour with an extremely poor prognosis in the presence of metastases. Significant progress has recently been made in the understanding of the molecular mechanisms leading to the vascular phenotype of renal cancer In particular, VHL disease constitutes a useful study model, as inactivation of the VHL gene leads to accumulation of HIF factor, inducing activation of genes such as: VEGF, PDGF, EPO, CaIX and TGF-alpha. The fact that VHL inactivation has been found in about 70% of sporadic renal cancers constitutes the best rationale to target the products of these genes. Candidate drugs currently target VEGF, VEGFR, PDGFR and tyrosine kinase receptors, which are necessary for intracellular signal transduction. The preliminary results of phase II trials in metastatic renal cancer, usually as second-line therapy, are very encouraging. The results of phase III trials will soon be available, but many studies are already evaluating these drugs either as first-line or in combination. Urologists have an opportunity to become familiar with these drugs by actively participating in trials of adjuvant therapy that will be initiated in the near future.

Waldenström's macroglobulinemia is a rare disease with an indolent clinical course. The median age of the affected patient is 65 years. Nevertheless, we report a case of Waldenström's macroglobulinemia revealed by a splenomegaly and severe pancytopenia, in a 51-year-old man without previous medical history. According to the recent consensus recommendations for the clinicopathological definition of Waldenström's macroglobulinemia, diagnosis was made through morphological and immunophenotypic data of medullary cells. The reduced survival of the patient is associated with the importance of the cytopenia.

Polycythaemia vera is an acquired myeloproliferative disorder characterised by a polycythaemia resulting of a clonal disorder arising in a multipotent hematopoietic stem cell. The increase of red cell mass exposes to a high risk of arterial or venous thrombosis and thus requires a cytoreductive treatment. An acquired genetic mutation in exon 12 of the JAK2 tyrosine kinase gene, leading to a substitution of a valine to a phenylalanine (V617F), has been described in most polycythaemia vera patients. This mutation increases the phosphorylation activity of JAK2, promotes the spontaneous cellular growth and induces erythrocytosis in a mouse model. Prevalence studies of V617F JAK2 mutation in different myeloproliferative disorders have found this genetic alteration in half of idiopathic myelofibrosis and in one third of essential thrombocythaemia. This finding is a huge progress in the understanding of polycythaemia vera physiopathology, it will be also an useful tool for the diagnosis of myeloproliferative disorders and it opens a new field for the development of targeted therapeutic approaches in these disorders.

Thyroid nodules are frequent and sometimes they pose a diagnostic and prognostic problem. DNA ploidy study and cell cycle analysis could be of value in the distinction between benign tumors and malignant tumors. Formalin-fixed and paraffin-embedded tissues from 69 patients with different benign and neoplastic lesions were investigated. Nuclear DNA content in thyroid cells was measured after Feulgen staining using SAMBA 200 image analysis system. A diploid DNA stemline was revealed in 75% of histologically proven benign thyroid tumors (15/20) and aneuploidy was found in 57.2% of malignant tumors (28/49). There is a significant correlation between aneuploidy and extra-thyroid extension (p=0.007) and bilateral and/or mediastinal lymph node metastasis (p=0.02). In the majority of benign tumors (19/20), the proliferation index was lower than 3% (< or =3%) however, this index value was higher than 3% (>3%) in more than 83% of malignant tumors (41/49) (p<0.001). The S phase fraction analysis revealed that the threshold of 14% divide the near whole of benign and malignant tumors (p<0.001). Our findings show that in follicular lesions, proliferation index and S phase fraction study appears interesting and helpful in the distinction between benign and malignant tumors, and aneuploidy seems more interesting in prognosis evaluation of these tumors.

Retinoic acid receptor beta (RARbeta) is a nuclear receptor often deregulated in tumors. An immunohistochemical study was conducted to examine the level of expression of this receptor in the nucleus of glial cell tumors (low and high grade glioma) as well as a study of the methylation status of the gene promoter coding this receptor on the same tumor samples. A comparison with normal tissue was done each time. 48 tumors were eligible for the study (15 glioblastomas, 20 grade III oligodendrogliomas and 13 grade II oligodendrogliomas). A constant decrease of RARbeta expression was found by comparison with normal tissue whatever the histological grade of the tumor, suggesting a deregulation of RARbeta gene expression. Methylation of RARbeta promoter gene was a rare event (12.5% of all cases), except for grade III oligodendrogliomas (20%), and is thus not a major event of this gene deregulation. Other reasons of this deregulation of RARbeta should be studied, such as loss of 3p24 heterozygoty, mRNA studies and RARbeta interactions with other retinoid receptors.

Loss of heterozygosity (LOH) of the short arm of chromosome 17 (17p) is one of the most frequent genetic alterations in human cancers. Most often, allelic losses coincide with p53 mutations at 17p13.1. However, in many types of solid tumors including sporadic breast cancers, ovarian cancers, medulloblastomas and small cell lung carcinomas, frequent LOH or DNA methylation changes occur in a more telomeric region at 17p13.3, in absence of any p53 genetic alterations. These results suggest that one or more tumor suppressor genes located at 17p13.3 could be involved in tumorigenesis. In addition, the 17p13.3 region has also been implicated in the Miller-Dieker syndrome (MDS), a severe form of lissencephaly accompanied by developmental anomalies caused by heterozygous gene deletions. Analyses of deletion mapping and CpG island methylation patterns have resulted in the identification of two tumor suppressor genes at 17p13.3, HIC1 (hypermethylated in cancer 1) and OVCA1 (ovarian cancer gene 1). HIC1 is a tumor suppressor gene that encodes a transcriptional repressor with five Krüppel-like C2H2 zinc finger motifs and a N-terminal BTB/POZ domain. Clues to the tumor suppressor function of HIC1 have come from the study of heterozygous Hic1+/- mice, which develop spontaneous malignant tumors of different types. Generation of double heterozygous knockout mice Hic1+/- p53+/- provides strong evidence that epigenetically silenced genes such as HIC1 can significantly influence tumorigenesis driven by mutations of classic tumor suppressor genes. This functional cooperation between HIC1 and p53 is interesting and recently, its has been demonstrated that HIC1 was involved in a certain feedback regulation for p53 in tumor suppression through the histone deacetylase SIRT1. However, despite the fact that epigenetic oncogenesis is one of the most vibrant areas of biologic research, the determinants between genetic versus epigenetic routes of tumor suppressor gene inactivation remain elusive.

The molecular analysis of chromosomal abnormalities associated with hematological malignancies allowed the identification of genes involved in theses rearrangements as well as of some recurrent mechanisms. Polymerase chain reaction (PCR) tools are now available to detect these rearrangements, allowing a better follow-up of these diseases. Chronic myeloid leukemia is a myeloproliferative disorder characterized by a reciprocal translocation t(9;22)(q34;q11) which results in a bcr-abl fusion gene. Retro-transcription polymerase chain reaction (RT-PCR) is used to detect bcr-abl to establish diagnosis and to monitor patients. We report here the results of 30 patients samples tested in the hematology laboratory at Pasteur Institute, diagnosed as chronic myeloid leukemia and monitored with RT-PCR. Our results highlight the interest of molecular tools to diagnose and monitor patients mainly when cytogenetic techniques are irrelevant such as cases with complex chromosomal rearrangements or when patients achieve Philadelphia negativity after treatment.

Breast cancer is a major health problem in developed countries. Pathological and clinical heterogeneity, partly responsible of therapeutic failures, reflects its poorly documented complex and combinatory molecular basis. Thorough molecular typing could allow not only better tackling that diversity and improving the current prognostic classifications, but also could help in the identification of new molecular therapeutic targets. The recently developed DNA microarray technology allows the analysis of the RNA expression of several thousands of genes simultaneously in a sample. Recent studies have shown the promising prognostic impact of gene expression profiling in breast cancer by identifying new prognostic subclasses unidentifiable by conventional parameters.

Chronic myelogenous leukemia is a model for the explaining between dysregulation of tyrosine-kinase and cellular transformation. BCR-ABL protein providing from the abnormal gene is the biological marker of the leukemic cells. It is the molecular counterpart of the chromosomal abnormality that is also called Philadelphia chromosome. Since BCR-ABL drives the leukemic proliferation, it became recently a specific target to develop the tyrosine-kinase inhibitors. These new specific drugs and their effects on the chronic myelogenous leukemia must be taken into account to explain the physiopathology of the disease.

Chronic lymphocytic leukemia (CLL) is the most common lymphoid hemopathy in elderly. Diagnosis of CLL is easily made with a full blood count and immunophenotyping, but there is an heterogeneity in clinical evolution. Until now, scheduling of treatment is based on Rai or Binet staging systems. These staging systems can not distinguish patients with a rapid evolution and thus who will need an earlier treatment. In order to detect these patients, it is useful to have some relevant markers to predict disease evolution. This article reviews recent biologic markers that can be used to evaluate long term prognosis of CLL patients.

Cancers induced by ionizing radiation have no particular specificity nor genetic remarkable signature, excepting numerous multideletions. They should therefore be studied in the general field of cancer biology in its broad sense. A gap remains between the initial events like the rather well identified genomic damage and the subsequent emerging cellular clone with cancer characteristics. Intermediate steps are generally described as accumulation of mutations and epigenetic modifications leading at one point to the malignant phenotype. However we have no clear nor understandable model on these steps of malignant transformation till now. It is quite possible that specific causes (tobacco, alcohol, radiations, chemical toxics) which produce different initial abnormalities then lead to (or accelerate the entry in) the common and same way as that resulting of accumulations of damage due to ageing. Genomic instability is certainly an important factor involved in the cellular drift leading to malignant transformation. We postulate that only cells having both a high telomerase activity and a low apoptotic activity may become cancerous. The hypothesis is that cancer results from a genome reprogramming of these cells due to an oncogenic mitotic pressure which induces a loss of the differentiation control. We propose to name anti-apoptosis, in contrast to apoptosis which is the programmed death, the ultimate process by which a cell loses its tissue-related properties. The oncogenic activation may propagate to primordial genes of development resulting in emergence of a subnuclear with tumoral activity. Bio-molecular studies of embryonic development and of genome re-programming will probably allow us to better understand the mechanisms of cancer.

Asbestos is known as mutagenic and carcinogenic for human and is responsible for many pulmonary diseases including asbestosis, bronchogenic carcinoma and malignant pleural mesothelioma. Occupational exposure to asbestos is involved in 70-80% of all malignant pleural mesothelioma. The later presents a growing challenge for both researcher and clinician. The diagnosis of malignant pleural mesothelioma is difficult and the current treatments did not show significant improvement of the survival. The increasing incidence of malignant pleural mesothelioma, its gravity and its human, social and financial consequences are of high concern in public health. In this paper we summarize the so far knowledge on cellular, molecular and pathophysiological events involved in genesis and development of malignant pleural mesothelioma. Finally, the paper also report recent data sourced from the study of malignant pleural mesothelioma transcriptome using high-throughput technologies such as gene expression array. These data should improve the accuracy of mesothelioma diagnosis and therapy.

In 50% of cases, polycystic liver disease is associated with autosomal dominant polycystic kidney disease, which is caused by mutations in the PKD1 and PKD2 genes that encode polycystin-1 and -2, respectively. These proteins form a polycystin-1/2 complex on the plasma membrane, including that localized on the surface of primary cilia, where they act as mechanosensors. Polycystin-1 acts as a (mechano)receptor of environmental signals, and polycystin-2 as a calcium channel mediating intracellular transduction. Isolated autosomal dominant polycystic liver disease is caused by mutations in PRKCSH that encodes hepatocystin, a protein of the endoplasmic reticulum, which may participate in the N-glycosylation and maturation of proteins addressed to the cell surface. Congenital hepatic fibrosis whether it is accompanied by bile duct dilatations (Caroli's syndrome) or not, may be associated with autosomal recessive polycystic kidney disease, which is caused by mutations in PKHD1 that encodes fibrocystin, a protein of primary cilia. Genetic defects in fibrocystin cause ciliary dysfunction, presently considered as a major pathogenic event in cystogenesis. Excessive cell proliferation, a hallmark of cystic biliary epithelium, occurs in combination with deregulation of the epidermal growth factor (EGF) and probably also estrogen receptors. EGF receptor antagonists inhibit kidney and liver cyst development in animal models, and are currently under investigation in phase I and II clinical trials in patients with autosomal dominant polycystic kidney disease.

Cerebral oligodendrogliomas represent more than 30% of glial tumors in adults. Mean age at diagnosis is 41 for grade A and 45(1/2) for grade B, epilepsy being the main revealing symptom (91.5% of A, 76% of B). Survival at 5, 10 and 15 years is respectively 75.5%, 51% and 22.4% for grade A (median: 136 months), and 45.2%, 31.3% and 0% for grade B (median: 52 months). It is influenced by age at diagnosis: median, before 40 years of age, is 12 years for A and 8(1/2) for B; between 40 and 60, is 12 years for A and 4(1/2) for B; over 60, is 4 years for A and 1(1/2) for B. In children, they represent less than 2.5% of cerebral tumors and include 23% grade A and 77% grade B (48.5% WHO grade II and 51.5% WHO grade III). Mean age at surgical removal is 9.5 +/- 5 years. One third are hemispheric, 2/3 are revealed by epilepsy. A complete surgical removal is performed in 60%. Mean survival is 13 years (154 +/- 20 months), with a mortality at 5 and 10 years of 60% +/- 9%, and a risk of recurrence of 54% +/- 9% at 5 years and 46.5% +/- 10.5% at 5 years. The main differential diagnosis of grade A oligo is dysembryoplastic neuroepithelial tumors (DNT). Inversely, thalamic locations, most often grade B, generally present with a motor deficit; complete removal can be achieved in only 15%. The only efficient treatment is chemotherapy, requiring search for chemosensitivity (1p19q deletion, expression of MGMT gene, analysis by MR-spectroscopy and TEP). Logically, surgical debulking should be as wide as possible, but with preservation of neurological and cognitive functions with the help of modern imaging progresses (fMRI, diffusion and perfusion MRI, tractography, PET) and operative techniques (navigation, cortical stimulation, and even opertaive MRI). Tumors presenting clinical and radiological progression should be removed. Operative mortality varies from 0 to 6%, transient morbidity from 20 to 25%, definit morbidity from 5 to 10%. Radiotherapy does not significantly modify survival whatever the delivered dose. The important point is the patient's radiosensitivity: survival is 148 months for radiosensitive patients versus 12 months for non responsive patients. Studies and development of pretherapeutic assays of tumoral radiosensitivity will be a fundamental research axis (PET, sample studies).