Tobacco is responsible for 80 to 90% lung cancer cases in industrialized countries. However, genetic factors are likely to be involved in lung cancer susceptibility. Some degree of familial aggregation of lung cancer is evidenced in most family studies. On the other hand, many tobacco carcinogens are metabolised by enzymes of the P450 cytochrome family. Two enzymes of cytochrome P450, CYP1A1 and CYP1A2, are inducible by tobacco carcinogens, and animal studies evidenced a genetic polymorphism of CYP1A1 associated with tumour occurrence after administration of a polycyclic aromatic hydrocarbon. In humans, an association between lung cancer and some P450 polymorphisms (CYP1A1, CYP2D6, CYP2E1) was suggested but the results of epidemiologic studies are discordant and difficult to interpret. In addition, there is a polymorphism of glutathione S-transferase isoenzyme (GSTM1) involved in carcinogen elimination; an association between this polymorphism and lung cancer has also been reported. Further studies on combined effects of these polymorphisms should allow an identification of sub-groups of individuals at high risk of lung cancer.

Presenting 3 personally examined cases, the authors underline the incidence and the characteristics of pheochromocytoma associated with Von Hippel Lindau disease. In conclusion, a systematic screening for Von Hippel Lindau disease-often unrecognized to day-must be done in every patient presenting with pheochromocytoma.

CYFRA is a new marker which measures a fragment of cytokeratin 19 in the serum by an immune radiometric method. The test is based on the preservation of the cytokeratin expression on the epithelial cells during the course of malignant transformation. In immuno-histochemistry the antibodies which selectively recognise cytokeratin react with all histological types of bronchial cancer. The presence of cytokeratin in the serum of patients suffering from cancer would be linked to their liberation during the course of cellular death. The threshold of specificity for CYFRA 21-1 is 3.3.3.6 ng/ml in a population suffering from benign respiratory diseases. The study performed in bronchial cancer produced the following conclusions: the marker is, above all, useful for epidermoid cancer; it is more discriminating than other markers to separate bronchial cancers and non-malignant respiratory disease. An elevated level of CYFRA 21-1 is predictive of advanced disease but does not permit any prediction as to inoperability. In 65% of cases, variations of CYFRA 21-1 are concordant with the stage of the disease during chemotherapy. Finally, elevated levels of CYFRA 21-1 predict a poor prognosis independent of the state of the disease.

This presentation allows us to understand the terminology used for oncogenesis by Molecular Biology investigators. Thanks to the minute description of the normal physiology of the cell cycle, its regulatory mechanisms and growth stimulating and inhibiting effects, we are able to understand the language used. We are now able to fill the gap in our knowledge and to establish the increasingly necessary relationship between routine practice and Molecular Biology.

We described a case of squamous cell carcinoma of the vulva in a patient with Morris' syndrome. In these patients, there is an increased risk of gonadal neoplasms. On the contrary, neoplasms originating from the vulvo-vaginal tract are very rare. Neoplasms arising from the neovagina have been reported. Therefore, a continued periodic surveillance of the external genitalia and the vagina is indicated.

Prognosis factors such as mutated or amplified oncogenes are used in the treatment of breast cancer. We have recently shown that the members of the PEA3 group (ER81, ERM and PEA3) from the transcription factor family of the ets genes are overexpressed in breast cancer tumors arising from MMTV-neu transgenic animals. Moreover, we have shown that ER81, and in a lesser extent ERM and PEA3, are not expressed in the estrogen and/or progesterone receptor-positive mammary cancer cell lines, whereas they are expressed in the receptor negative ones. Our research interest in now focused on the role(s) of these oncogenes in the development and the regulation of breast tumors.

The role of estrogens as promoters of breast carcinogenesis has been well established while their action in tumor invasion appears more complex. Breast cancer cells without estrogen receptor (ER) are generally less differentiated and more aggressive than those containing function ER. Moreover the reexpression of ER by transfection in ER-negative cell lines inhibit their metastatic potential. These results suggest a protective role of ER in the metastatic progression of breast cancers. Studies of the underlying mechanisms of this effect may open new therapeutical strategies.

Numerous acquired genetical mutations are now well described by molecular biology and seem to be related to tumour progression. K-RAS mutation is of interest in colorectal cancer where it could be correlated to an aggressive tumoral behaviour leading to a high risk of recurrence or metastasis.

T cell prolymphocytic leukemia (T PLL) is a rare variant of mature lympho-proliferative disorder. The main physical sign is a gross splenic enlargement contrasting with no enlargement of lymph nodes. Skin involvement is found in 30 p. 100 cases. Twenty-one cases of cutaneous lesions of PLL have been reported, mainly with T PLL, only 2 cases of B PLL: Clinical lesions are polymorphous; histology shows a dermal prolymphocytic infiltrate. The main cytogenetic abnormalities are: translocation (14; 14) (q11; q32), inversion of chromosome 14 (q11; q32), isochromosome 8q.

A 14-year-old girl consulted for multiple breast nodules which were found to result from Cowden's disease, also called multiple hamartomatosis. Mammography and sonography examinations were completed with nuclear magnetic resonance imaging after injection of paramagnetic contrast product. Cowden's disease is a rare condition resulting in the development of tumors in genodermatous tissue; The cause remains unknown. In cases involving the breast, cutaneous lesions are markers of precancerous development since cancer occurs in 28 to 30% of these cases.

Myeloblastin (mbn) is a serine protease involved in the control of growth and differentiation of human leukemic cells. In the promyelocytic-like human leukemia cell line HL-60 this protease is inhibited during retinoic acid (RA) induced differentiation. The t(15;17) translocation, specifically associated with the human acute promyelocytic leukemia (APL), fuses the retinoic acid receptor alpha (RAR alpha) to a novel gene PML generating the hybrid protein PML-RAR. We have shown that while mbn was early down-regulated in HL60 cells treated with all trans RA, the inhibition of this gene was considerably delayed in NB4 cells, which carry the t(15;17) translocation, upon treatment with the same inducer. This observation suggested that the changes in the myeloblastin regulation by RA found in NB4 cells could be ascribed to the presence of the fusion protein PML-RAR. To verify this hypothesis we have cloned the putative promoter region of mbn gene. Transactivation properties of endogenous retinoic acid receptors on this region have been tested in transfection experiments of HL60 and NB4 cell lines before and after treatment with all trans RA. We found that RA induced a significant inhibition of the luciferase reporter gene in HL60 cells. In contrast, a strong stimulation of luciferase activity was observed in NB4 cells treated with RA. The analysis of the promoter region allowed us to identify a new response element for retinoic acid receptors, named mREpal, which is probably affected by the product of t(15;17) translocation.

Acute promyelocytic leukemia is a key model system in Cancer biology. Its ability to differentiate upon exposure to retinoic acid constitutes the first example of differentiation therapy. The molecular basis of leukemogenesis is the PML/RAR fusion resulting from the t(15, 17) translocation. The fusion protein likely acts through interference with the function of nuclear receptors (resulting in a differentiation block) and also through interference with PML which appear to be a growth suppressor. The exquisite sensitivity of this disease to retinoic acid represents the first example of a therapy directly targeted at a specific and causative genetic lesion.

Usual treatments combining surgery, radiation therapy, chemotherapy and hormonotherapy are poorly effective. The immunotherapy gave and objective response rate of 25% but is associated with many side effects. Multidrug resistance (MDR) can be explained, in part, by an mdr1 gene overexpression in renal carcinoma. The MDR is related to expression of a 170 Kda membrane glycoprotein, the so-called P glycoprotein (Pgp). This protein is able to extrude from cytoplasm drugs with various structures and mechanisms. Reversal compounds capable of inhibiting Pgp, given with antineoplastic drugs, could be able to increase their intracellular concentrations. Nevertheless, renal cell carcinomas are characterized by their multifactorial resistance and a better knowledge in this field will allow to design new circumvention resistance to chemotherapy.

A complex translocation involving chromosome 6, 8 and 9 [t(6;9;8)(p23;q34;q22)] associated with other structural and numerical abnormalities was observed on bone marrow karyotype of a woman suffering with acute myeloblastic leukemia (AML2). Fluorescence in situ hybridization agreed with the conventional cytogenetic interpretation by showing that a part of chromosome 6 short arm was inserted on the rearranged chromosome 9 resulting in the t (6;9) usually encountered in AML.