Carotid body tumors are rare hypervascular lesions arising from neural crest paraganglion cells.

Insulin resistance is observed in several diseases such as non insulin dependent diabetes mellitus (NIDDM) or polycystic ovarian syndrome (PCOS). To understand genetic determinism of this abnormality we have developed a multidisciplinary approach including selection of phenotypes with insulin resistance confirmed in vivo by minimal model of Bergman and characterization of cellular defects in insulin action on circulating erythrocytes and monocytes. Exploration of variability in candidate genes by direct sequencing in some genetic syndromes of severe insulin resistance and acanthosis nigricans (mainly the Type A syndrome) revealed mutations of the insulin receptor gene associated with major defects in insulin binding or kinase activity. In other rare genetic syndromes or patients affected by NIDDM or PCOS defects appear to be located at post-receptor level, where IRS (insulin receptor substrate) genes are the most attractive candidates. Prevalence of some allelic variants suggested a potential role of IRS genes in insulin resistance, although their involvement in the pathogenesis of NIDDM remains controversial. Genotype-phenotype correlations in first degree relatives of an index case caring the Type A syndrome, suggested that association of allelic variants of IRS-1 and IRS-2 with insulin receptor mutations contribute, by synergistic effects, to phenotypic expression of defects in signal transduction. These mechanisms through genetic epistasis, involving several genes in insulin action, fit better with the polygenic nature of current forms of NIDDM and represent a good model in the study of pathogenesis of insulin resistance.

The molecular diagnosis of genetic abnormalities responsible for genetic predisposition to breast cancer is made difficult by the large size of the genes and the diversity of gene mutations found within these genes. The molecular diagnosis of responsible mutations requires the implementation of particular analytical methods, for which we give two examples, the protein truncation test and the direct sequence analysis of the cDNA. Results obtained with these two methods demonstrate the interest of studying the sequence of messenger RNA expressed by predisposing genes. The study also describes an abnormal splicing and two rearrangements responsible for genetic predisposition to breast cancer.

Suicide gene therapy consists of transferring into tumor cells a viral or bacterial gene encoding for an enzyme which converts a non-toxic product into a lethal drug.

Oncogenesis is a multistep process, which is the outcome of the accumulation in a single cell of genetic and epigenetic events. The events alter proto-oncogenes, which are converted into oncogenes with gain of function and tumor suppressor genes with loss of function. Cellular mechanisms (e.g. apoptosis) protect tissues against the malignant transformation of cells and limit, for each tissue, the combinations of efficient genetic alterations. The number of genetic events required for conversion to malignancy is still debated, but, at least in the case of many solid tumors (e.g. colon carcinomas), this number may be as high as seven to eight, which implies that a genetic instability occurs during cancer progression. In most cancers the probability of occurrence of oncogenic genetic events is increased by exposure to behavioural and environmental factors. In the case of chemical carcinogens, the dose-effect relationship is strongly affected by their effects on cellular proliferation, which should be taken account into when the experimental data of animal experiments are extrapolated to human exposures. When non-genotoxic carcinogens are considered, a threshold in the dose-effect relationship is generally observed. For genotoxic carcinogens, it is hard to prove experimentally that a threshold exists and linear no-threshold relationships are generally used to evaluate permissible levels of human exposures.

Multiple Endocrine Neoplasia type 1 (MEN 1) is an autosomal dominant syndrome characterized by neoplasia of the parathyroid glands, the endocrine pancreas and the anterior pituitary gland. Recently the identification on chromosome 11 (locus q13) of the gene responsible for MEN 1 has allowed direct genetic diagnosis of MEN 1-affected family members. To date almost 300 families have been described and genetically characterized. The genetic etiology of most pituitary tumours remains unknown. Pituitary adenomas can develop sporadically or as a part of multiple endocrine neoplasia type 1. In this review, the recently published data on the pathology of the MEN 1 syndrome will be summarized. The clinical, morphological and genetic aspects of sporadic and MEN 1-associated pituitary adenomas will be outlined.

The interaction of oestrogens with their intra-nuclear receptor is now recognized in its tri-dimensional aspects. A new receptor, ER beta, has been cloned and new non-genomic oestrogen effects have been reported. Hence, a better understanding of physiological mechanisms or of pathophysiological aspects, such as phyto- and xeno-oestrogens' influence on the organism, is possible. New compounds, belonging to the SERM family, are being explored. Raloxifene is now available for the prevention of post-menopausal osteoporosis. Tamoxifen has been associated with a beneficial effect for the primary prevention of breast cancer in a high-risk population. The understanding of genetic susceptibility could contribute, to better define women at risk. A dedicated primary prevention strategy in women with a high risk of breast cancer coupled with early detection through mammography will continue to improve the prognosis of this hormono-dependent cancer.

We report an unusual case of gastric tumor: a stromal tumor with osteoclast-like giant cells. This type of cells has been described in epithelial tumors, especially in adenocarcinoma of the pancreas, lung, thyroid and breast. It has also been reported in smooth cell tumors such as uterine leiomyosarcoma and malignant fibrous histiocytoma. In our patient, this gastric stromal tumor with osteoclast-like giant cells was diagnosed in a man with adenocarcinoma of the colon in the context of a familial cancer syndrome. This is the first report of stromal tumor with osteoclast-like giant cells associated with Lynch syndrome.

Pulmonary lymphangioleiomyomatosis is characterized by a proliferation of abnormal smooth muscle cells in peribronchial, perivascular and perilymphatic areas leading to cystic destruction of the pulmonary parenchyma. Recent clinical series of LAM have been helpful in better describing the various clinical and radiological forms of the disease, although our understanding of the pathophysiological mechanisms of LAM remains very limited. Significant progress has been noted in recent years with the discovery of probable antigenic and genetic similarities between pulmonary lymphangioleiomyomatosis, Bourneville tuberous sclerosis and renal angiomyolipoma. The proliferating cells in LAM share with normal smooth muscle cells their reactivity with desmine, vimentin and actin but certain are different by their reactivity with the monoclonal antibody HMB45, a common antigen marker of melanocyte differentiation cells, clear-cell lung carcinomas or renal angiomyolipomas. A loss heterozygosity in the region of the TSC2 gene in renal angiomyolipomas has been demonstrated in association with pulmonary lymphangioleiomyomatosis. The TSC2 gene is particularly implicated in the pathogenesis of Bourneville tuberous sclerosis.

In oncology, flow cytometry (FCM) and image cytometry (ICM) are commonly used to detect DNA aneuploid cell populations in solid tumors. Agreement between these two approaches is good. The use of both techniques in association minimizes the rate of FCM and ICM false negatives and gives better DNA pattern characterization, particularly for detection of any tumoral component in the FCM DNA diploid peak. Nevertheless, discrepancies exist between the FCM and the ICM DNA index values: the ICM DNA index is often greater than the FCM DNA index. The aim of the present study was to establish a cytogenetic DNA index by determining the chromosomal ploidy using a molecular cytogenetic approach and to compare it to the FCM and ICM DNA indexes. We present here the fluorescence in situ hybridization (FISH) technique we have adapted to the study of breast cancer in order to count the number of copies of the 22 + X human chromosomes in interphasic nuclei. This was achieved using a panel of 21 indirect FITC labeled probes which recognize specific chromosomic DNA sequences. Preliminary results obtained from DNA diploid and DNA aneuploid tumors are discussed.

Burkitt's lymphoma has the highest incidence of any childhood cancer in equatorial Africa. Geographic distribution appears to be related to climatic conditions and coincides with areas of endemic malaria. These tumors are characterized by reciprocal translocation from chromosome 8 at or near the c-myc locus to either the immunoglobulin chain locus on chromosome 14 (80 p. 100 of cases) or one of the light chain loci on chromosome 2 or 22. As a result of this translocation, transcription of the protooncogene c-myc is activated. Deregulation of c-myc could play a major role in onset and development of the tumor. Study of Burkitt's lymphoma led to the discovery of the first association between viral infection and tumor development in humans. The Epstein-Barr virus is contained in all endemic Burkitt's lymphoma cells, thus implicating it as a likely etiologic factor. Viral expression is reduced essentially to small non-coding RNA, non-polyadenilates, and EBERs (10(6) copies per cell) and a nuclear protein EBNA1 which is indispensable for maintenance of the Epstein-Barr virus genome in infected cells. Expression of EBNA in transgenes leads to lymphoma in mice and could play a role in the expression of the c-myc gene involved in translocations.

Ataxia telangiectasia is a multisystem disease with an autosomal recessive inheritance. It is characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, humoral and cellular immunodeficiencies and high incidence of neoplasia and radiosensitivity. A 5 year retrospective survey included 24 patients belonging to 17 families. Cerebellar ataxia was the first clinical symptom and was usually noticed when the child began to walk. Mean age of onset was 2.9+/-1.8 years. Oculocutaneous telangiectasia was present in 17 cases and appeared between 2 and 8 years and then spread in a characteristic symmetrical pattern. When ocular telangiectasia was absent (6 cases), the diagnostic of ataxia telangiectasia was retained on oculomotor apraxia (2 cases), recurrent sinopulmonary infections (3 cases) and/or a sib with typical ataxia telangiectasia (1 case). Recurrent sinopulmonary infections, absence or low serum level of IgA (78 p.100) and lymphopenia revealed immunodeficiency. Among 12 patients, chromosomal instability was observed in 5. Balanced rearrangements involving chromosomes 2, 7, 14, 22, 1, 3 and 11. The responsible gene, ATM, encodes a large protein kinase with a phosphatidylinositol 3-kinase-like domain. Ataxia telangiectasia patients have a 100 fold higher risk of cancer than the general population. We reported, in the same family two patients who developed neoplasia, (lymphoma and leukemia). During follow-up, a progressive worsening was observed in all cases. Three patients have died.