Lung as well as head and neck cancer represent an important public health problem worldwide, with lung cancer being the leading cause of cancer death in western countries. Although early stage disease is often curable with surgery or radiotherapy, the majority of patients present with advanced disease in which despite advances in combined modality therapy the outcomes have not dramatically improved. Furthermore, patients cured of their initial early stage lung or head and neck carcinoma are at high risk for development of second primary tumors, which pose the main threat to their survival. An alternative approach in reducing the incidence and thus mortality of these cancers is chemoprevention, the use of agents to reverse, halt or delay carcinogenesis. The carcinogenesis process in lung and head and neck cancer results from a dysregulation of cellular proliferation, differentiation and cell death resulting from field-wide exposure of the upper and lower airway track to tobacco smoking. This review article presents main data regarding the actual understanding of lung and head and neck carcinogenesis, as well as results of major chemoprevention trials in this field.

Biological diagnosis of pheochromocytoma is relatively easy in those cases releasing great amounts of catecholamines with strong clinical features; instead, diagnosis could be more problematic in atypical or asymptomatic familial pheochromocytoma with small tumors secreting low catecholamine amounts. Several plasma and urine adrenergic markers must be used to confirm the clinical suspicion. We have discussed the biological data of three totally asymptomatic pheochromocytomas (cases no 2, 3, 4) and one case with a very discrete clinical manifestation (no 1). Three patients had very small tumors (4, 7 and 25 g) secreting preeminently adrenaline, one patient had a 45 g adrenal incidentaloma without clinical expression. Our study shows that, in these special cases, except for an inconstant increase of adrenaline, plasma and urine catecholamines and urine VMA can be normal. The most useful markers are plasma and urine methoxyamines. However, plasma methoxyamines are the most sensitive because their increase over reference values is by far greater than in urines. Several factors may explain these findings: a low tumoral secretion, the nature of the released amine, the short half-life of catecholamines in plasma and, in some cases, the involvement of intratumoral catecholamine metabolism. Analysis of the ratio NMN/MN in plasma provides an additional diagnosis tool to reveal adrenaline secretion abnormalities.

Comprehension of cell cycle regulation mechanisms has progressed very quickly these past few years and regulators of the cell cycle have gained widespread importance in cancer. This review first summarizes major advances in the understanding of the control of cell cycle mechanisms. Examples of how this control is altered in tumoral cells are then described.

Adrenocortical carcinoma remains a challenge for the therapeutist; prognosis is ominous. Various abnormalities playing a pathogenetic role have been recently described in adrenocortical tumors. Among them, dysregulation of the IGF system and imprinting mistakes at the 11p15 locus play a determining role in malignant transformation of adrenocortical cells. These markers of the malignant phenotype might markedly improve our diagnosis and prognosis abilities.

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) is an aggressive form of acute leukemia that children ALL. Between 1991 and 1998, eight cases Ph+ ALL (7 males and one female) were diagnosed in our institution by successful cytogenetic studies. Median age was 37 years (range, 1-60 years). Leukocyte count was more than 50 x 109/l in 5 cases. According to the French-American-British (FAB) criteria, six patients were classified L1 and two L2. The Ph+ as sole anomaly was seen in 2 patients (25%), while additional chromosome changes were observed in 6 cases. Complete remission was achieved in 5 cases (62%) and relapse was observed in all cases? The 2-year survival rae was 25% confirming the worse prognosis of this leukemia when treated with standard chemotherapy.

It is often difficult to establish the etiological diagnosis of erythroderma because clinical findings and immunohistology cannot always distinguish between lymphomatous erythroderma and inflammatory erythroderma. The purpose of this work was to assess the contribution of PCR-DGGE for detecting clonal T-cell receptor gamma gene rearrangement to the etiological diagnosis of erythroderma.

Mutations of the p53 gene are the most common genetic alteration in malignant human tumors. A cyclin-dependent kinase inhibitor, p21WAF1/CIP1, is thought to be an important mediator of p53-induced cell cycle arrest. Although numerous studies have reported p53 expression and mutation in colorectal cancer few of them have correlated p53 expression with that of its downstream effector p21 and with the proliferation index as measured by expression of the Ki67 nuclear antigen. We studied p53, p21 and Ki67 expression by immunohistochemistry and molecular biology in 35 colorectal carcinomas. We compared these findings with each other and with clinical factors. Sixty three percent of tumors expressed p53 whereas seventy one percent expressed p21WAF1/CIP1. In adenocarcinomas, p21 staining was heterogeneous: p21-reactive cells were seen in the most differentiated areas. There was no correlation between p21WAF1/CIP1 and p53 expression, p53 mutation, Ki67 expression or clinical factors such as sex or location of the tumor. On the other hand, there was a statistical relationship between p21 expression and survival: our results indicated an association between high p21 expression and lower stages p21WAF1/CIP1 appears to be induced independently of p53 in these tumors and may be associated with differentiation rather than proliferation.

EPIDEMIOLOGIC DATA: The frequency of malignant melanoma, by far the most fatal skin cancer, has increased by a factor of approximately 15 in the past 60 years. The factors underlying this rapid increase are incompletely understood, although ultraviolet radiations are likely strongly implicated. Epidemiologic studies demonstrate the role of altered patterns of sun exposure, and overexposition to UVA radiation, as confirmed by experimental data on animal models. BIOLOGICAL ASPECTS: Melanin produced by melanocytes has a photoprotective function in the skin, whereas UVB-induced DNA damage enhance the repair capacity of these cells. However, this photoprotective effect is not induced by intense intermittent sun exposure. In addition, melanocytes demonstrate resistance to UVB-induced apoptosis and are thus at high risk for incorporating UV-induced mutations. MOLECULAR ASPECTS: Different mutations in susceptibility genes (CDKN2A, INK4), or in genes implicated in control of cell cycle or maintenance of cell integrity (DNA repair) are involved in initiation and promotion steps of melanocarcinogenesis. Moreover, tumor progression is stimulated by UVB through the activation of different target genes that are implicated in control of melanoma environment (immune surveillance, angiogenesis, growth factors...).

Suppression subtractive hybridization (SSH) was used to isolate genes that were differentially expressed in anaplastic lymphoma kinase (ALK)-positive and ALK-negative anaplastic large cell lymphoma. In addition, this approach was applied to Hodgkin's disease cases with different clinical outcomes. SSH combines a normalization step that equalizes the abundance of cDNAs within the sequences to be tested and a subtraction step that excludes the common sequences between the target and the control. In a model system, the SSH technique enriches for rare sequences up to 5,000-fold in one round. We have isolated several genes whose expression varied significantly with regard to the tumour subtypes. There were different genes with known or unknown functions. We aim to compare the results of the SSH approach with those obtained with high density filters. In a near future, we would like to design DNA chips specific of each pathology that could be used for clinical purposes (evaluation of prognosis and therapeutic response).

Although the use of asbestos has been banned in most industrialized countries, it is still a major public health concern. Asbestos fibers are mutagenic and carcinogenic for humans, classified as "carcinogen category 1 (T, R45: can cause the cancer)" in the 25th adaptation of the directive 67/548/EEC. In France, asbestos is thought to be responsible each year for many pulmonary diseases: pleural plaque, bronchogenic carcinoma and mesothelioma (malignant tumor of pleura). In order to better understand the transformation process of pleural cells, we compared the gene expression of mesothelium cells (Met-5A) and mesothelioma cells (MSTO-211H) using high-density filter array (588 genes) and microarray (6.969 genes). Results of both technologies were compared and expression levels of several genes were confirmed by quantitative RT-PCR. Data analysis with GemtoolsTM 2.4 software allows us hierarchical classification of genes of known functions by enzyme, function and pathway clusters and leads to characterize both malignant and normal phenotypes. Finally, the comparison between the two cell lines provides new markers of mesothelioma and pleura. They could be useful for diagnostic, prognostic and therapeutic.

Neuroblastoma is a very common solid tumor which arises in childhood and shows an extreme heterogeneity at the clinical, histological and genetic levels. Besides age and stage, N-myc amplification and 1p deletion are prognostic factors of the disease: in Europe, these genetic markers are used to conduct therapy. In France, N-myc amplification is a factor of bad prognosis which leads, in all forms of the disease including localised forms and metastatic forms of children aged of less than 1 year, to a myeloablative treatment with autologous hematopoietic stem cells transplantation. By contrast, N-myc amplification has no impact on the survival of children aged of more than 1 year with a poor prognosis (30% overall survival, 5 years) but this genetic abnormality is taken into account to treat primary tumor of these patients. In an attempt to find out prognostic factors of these aggressive forms of the disease, various pathways (apoptosis, differentiation angiogenesis, detoxication, immune response) have been recently surveyed, but studies have been carried out on a limited number of genes. Moreover, experimental models of human metastatic neuroblastoma have been obtained in which variations of genes transcript levels involved in these pathways, are observed. The current break-through of cDNA microarrays allows to develop a dynamic transcriptomic scanning of these models as well as of tumors and bone marrows from patients upon conventional chemotherapy. This technology will enable: i) to define molecular entities of the metastatic disease; ii) to apply adapted treatment; iii) to develop new therapeutic strategies.

Genetic epidemiology studies have suggested the responsibility of genetic factors in prostate cancer susceptibility. The development of genomic and high throughput genetic studies has allowed the recent identification or localization of such susceptibility genes. Furthermore, these technologies have contributed to outstanding advances in somatic genetics of prostate cancer. The goal of the present review is to disclose contributing technologies to and results of genetic studies of prostate cancer.

Breast cancer is the most frequent and deadly cancer of women. Its great heterogeneity makes prognosis and response to current treatments highly variable and difficult to predict. Mammary oncogenesis remains poorly understood. These issues should benefit from recent development of techniques capable of large-scale molecular analyses. The use of cDNA array techniques allows for the simultaneous analysis of the mRNA expression levels of thousands of genes in mammary tumor cell lines and breast tumors. Expression profiles will help classify tumors and provide new prognostic tools and potential therapeutic targets. They will also boost our knowledge of the molecular events responsible for the development and progression of this cancer.

Recent technological advances (e.g. various DNA arrays and chips) allow the measurement of expression level (mRNA abundance) for thousand of genes simultaneously, over multiple conditions or time. Initially developed and tested on model systems such as yeast or in vitro cell line cultures, these techniques have recently begun to be applied to the analysis of human cancers. Initial results are promising, and large-scale gene expression profiling is now expected to become a clinical tool for better tumour identification, prognosis, and optimal treatment design. It is thus important that clinicians become familiar with the theoretical principles underlying the interpretation of gene expression profiles as used in three different contexts: gene discovery, tumour class prediction, and molecular diagnosis. This is the purpose of the present article.

Genetic instability results, in a large majority of solid tumors, in deep chromosomal rearrangements. However, because chromosomal instability produces highly complex caryotypes, rarely showing stereotypic aberrations, it has not been possible to characterize solid cancers according to specific patterns of chromosomal rearrangements. This contrasts with the situation in hematological malignancies, where cytogenetics has allowed to lay out the basis of a renewed classification. New insights have been brought by the development of comparative genomic hybridization (CGH). This molecular cytogenetics approach was originally devised to detect regions in the genome of tumor cells undergoing quantitative changes, i.e. gains or losses of copy numbers. The large body of studies based on CGH show that solid tumors undergo frequent gains and losses and that every chromosomes show at least one region of anomaly. Furthermore, different tumor types present distinct CGH patterns of gains and losses. These observations favor the idea that it may be possible to type human solid cancers according to their patterns of genomic aberrations. However, despite the fact that a number of CGH based studies present data suggesting that different tumor types or cancers at different stages of evolution show distinct patterns of gains and losses, it has proven difficult to be conclusive. This can be mainly attributed to the lack of spatial resolution of CGH. Indeed, CGH uses metaphase chromosomes as hybridization targets and therefore its resolution is at the level of chromosomal banding. The recent adaptation of DNA array technology to CGH will allow to pass this limitation. In DNA array based CGH (array-CGH) metaphase chromosomes have been replaced by spots of cloned DNA. These DNA clones may either be genomic (BACs, YACs or cosmids) or coding (cDNAs). The resolution of array-CGH is therefore determined by the size of the cloned DNA insert (100 Kb for BACs, 1-2 kb for cDNAs). Data corresponding to each of these clones is or will be in a near future linked to DNA sequence data. Hence, in a near future, array-CGH will allow to increase the resolution from a cytogenetic level to a molecular level. Finally, because array technology is highly adaptable to automation, going from classical CGH to array-CGH will produce a quantum leap in throughput.

The Human Genome Project has allowed considerable progress in the construction of physical and genetic maps and the identification of genes involved in human sicknesses. The accelerated accumulation of biological information and knowledge is due in large part to the sequencing projects of other organisms, which in fact paved the way for the Human Genome Project. In parallel, recently developed techniques which take advantage of genomic sequences allow large scale molecular analyses resulting in the functional annotation of many of the proteins represented by these genes. This is the goal of functional genomics. These progresses are at the origin of the present revolution in biomedical research. DNA microarrays are playing a dominant role compared to the other developing technologies since they are relatively easy to make and use and are applicable to numerous scientific inquiries. They allow the simultaneous analysis of several thousands of genes in biological samples from sick or healthy tissues, at the genome or transcriptome level. The data obtained is expected to result in major advances in the health sciences. In addition to an improved understanding of the complex molecular interaction networks of healthy cells and tissues, a more precise genetic characterization of the molecular mechanisms involved in pathology should result in the identification of new therapeutic targets and the development of new medicines. The genetic profiles thus obtained should also permit the definition of new pathologic subclasses not recognizable by traditional clinical factors, as well as new markers for susceptibility to certain illnesses, and new prognostic markers or methods of predicting responses to treatment. In this article, we present the different approaches and potential applications of DNA microarray technology, in particular as applied to cancer research.