Familial forms of renal urinary tract and testicular cancers are rare (1 to 2%), in contrast with prostatic cancer (20%). Among these familial cancers, hereditary forms related to a genetic abnormality transmitted to the offspring are now better known and are of particular practical value for the clinician. Their diagnosis can modify the modalities of the patient's treatment in view of the multifocal nature of the tumours within the same organ and/or the frequent bilateral involvement of paired organs. The risk of transmission of the deleterious gene to the offspring requires information and close surveillance of relatives to allow early diagnosis and a better prognosis. When the predisposing gene is known, surveillance can be exclusively directed towards subjects possessing the deleterious gene in view of the increased cancer risk compared to the general population. This is the case for renal cancer in Von Lippel Lindau disease, and nephroblastoma and exceptional tumours of the urinary tract in Lynch syndrome. In the case of prostatic cancer, the most frequent familial cancer, in which hereditary forms represent 9% of cases, the predisposing gene has not been identified, which means that screening should be proposed to all male members of the family over the age of 40 years, due to the earlier age of development of these forms.

The Philadelphia chromosome (Ph) resulting from translocation t(9;22)(q34;q11) is observed in more than 90% of patients with chronic myeloid leukemia (CML). Its molecular consequence is the genesis of a fusion gene BCR-ABL between the 5' sequences of the BCR gene (chromosome 22) and the 3' end of the ABL gene (chromosome 9). Fluorescence in situ hybridization (FISH) using specific DNA probes provides a useful tool for the detection of t(9;22) and BCR-ABL rearrangement. We report our results using the FISH technique for t(9;22) assessment in the hematopoietic cells of patients with Ph-positive CML. The DNA libraries pBS 9 and pBS 22 containing multiple sequences derived from chromosomes 9 and 22 have been used to identify t(9;22) in metaphase cells. The cos bcr-51 and cos abl-18 probes that hybridize to unique sequences specific to the BCR and ABL genes have the ability to detect the BCR-ABL rearrangement in metaphase cells as well as in interphase nuclei. FISH is a sensitive and specific technique that represents a valuable complement to conventional cytogenetics. The BCR-ABL rearrangement can be detected in metaphase spreads of insufficient quality or from interphase nuclei in the case of terminally differentiated cells or of cells which do not divide in vitro. When the efficiency of hybridization and detection is good, a large number of cells can be analyzed. This is of major significance in assessment of response to treatment and definition of a cytogenetic remission. However, interphase cytogenetics may be difficult due to variations in signal resolution and background level. The FISH technique can also be used to detect the BCR-ABL rearrangement in cases of Ph negative BCR-ABL positive CML.

Echography was prospectively performed in 345 black African female patients with pelvic masses which had been clinically detected in some cases. The women were between 11 and 65 years old. The aims of this study were to list the pelvic masses observed in black. African women, to record any potentially distinguishing features and to evaluate the sensitivity and the specificity of echography as applied here. A total of 477 masses were listed. Ovarian masses were the most frequent (56.66%) followed by uterine masses (31.45%). Most masses were benign. We observed only two cases of ovarian cancer. The sensitivity was 100% and the specificity was 97.69%. Eleven cases (2.3%) of the ultrasound diagnoses did not correspond with the final diagnoses. As for distinguishing aspects, these patients were younger than European patients-this was particularly true for patients with fibroid masses (a range of 31 to 40 years compared to 40 to 50 years). Genetic factors in these patients could explain the high rate and early appearance of fibroids. Because the diagnosis of vaginal masses is well established by clinical examination rather than by echography, this lesion was rarely observed. The most frequent clinical complaint was pelvic pain (36.94%), followed by pelvic mass impression (28.65%). We found high rates of both past histories of miscarriage and abortion (60.7%) and postabortion pelvic hematoma. The hematomas comprised 45.4% of the non-genital pelvic masses. Misdiagnosis of pyosalpinx was often a source of diagnostic error. Thus, to avoid false diagnoses of pyosalpinx in evaluating pelvic masses with a void in ultrasound, the possibility of an infectious episode should be evaluated by definitive questioning. Ultrasound examination is of value in evaluating the pelvic masses of women; however, this should be considered within the appropriate disease context.

To initiate a genetic linkage study in order to localize one or several predisposition gene(s) for hereditary prostatic cancer (PC), as various epidemiological studies have demonstrated a possible family aggregation in about 25% of cases. A family segregation study [14] has also shown that a genetic predisposition, with autosomal dominant transmission and high penetrance (88% at 85 years) could be responsible for 9% of all PC.

Alterations in the p53 gene are found in 20% to 40% of breast cancers and are generally associated with factors of adverse prognostic significance. In most instances, point mutations modify the confirmation of p53, causing the gene to accumulate in the nuclei of tumor cells. These alterations can be detected via molecular analysis or immunohistochemical methods. More recent studies have demonstrated that accumulation of the p53 protein in tumor cells may induce an immune response with presence of anti-p53 antibodies in the serum of cancer patients. Assaying serum anti-p53 antibody is a new approach to investigation of the status of the p53 gene in a tumor.

Mutation of the p53 tumor suppressor gene is the most commonly observed gene alteration in human cancers. In order to identify new prognostic factors and tumor aggressiveness in squamous cell head and neck carcinomas, we analyzed 50 node metastases and 28 primary tumors including 13 matched specimens for p53 alterations. Mutations were found in 54 (69%) tumors, 76% of which were missense, 9% were nonsense and 15% were microdeletions or microinsertions. Twenty-five mutations were transitions mostly G-->A (40%) and 20 were transversions mostly G-->T (25%) thus confirming the role of tobacco carcinogens in the induction of these mutations. For eight patients mutations were observed in matched primary tumors and metastases, indicating clonal dissemination of tumor cells in most of these carcinomas. Furthermore the incidence of mutations was not different in primary tumors and node metastases indicating that this gene alteration was not related to the metastatic dissemination. No correlation was found between mutation and clinical parameters, the 8-year survival rates were not different (log rank test: P = 0.49) in patients with and without mutation. There was a good correlation between p53 mutation and protein overexpression (Fisher's exact test: P < 10(-4). Interestingly, immunostaining was also observed in basal cells from normal mucosa and in early lesions adjacent to the primary tumor in 11/15 specimens irrespective of the presence of mutation in the corresponding tumors. p53 protein overexpression may therefore constitute a biomarker for early stages of carcinogenesis of the head and neck epithelium.

Ataxia telangiectasia (AT) is a genetic disorder with an autosomic recessive transmission. Occurring during childhood, it affects different organs and/or systems. Physiopathology is still unclear. The first clinical signs are evident early in childhood and evolution always leads to death. The secondary cause of mortality in 10 to 15% of the affected is the development of cancers. Genetic predisposition to cancer for homozygotes, as well as for heterozygotes, is one of the most remarkable aspects of this disease. For heterozygotes the risk of cancer is three times that of the norm. The gene responsible for the disease has been cloned. Its function may resolve some questions, and provide the link between degenerative process, cancer susceptibility and immunodeficiency evident in AT patients.

Although prognosis of malignant gliomas did not change dramatically for the last 15 years, tumorigenesis is much better understood. The study of the genetic alterations occurring in these tumors allowed to recognise the most critical genes involved, which are either overexpressed oncogene, or inactivated tumor suppressor gene. Gene therapy is a natural outcome of such progresses. One way of tumor gene therapy is based on correction of genetic defect either by introducing the missing tumor suppressor gene or by blocking overexpression of an activated oncogene. Alternatively, "destructive" gene therapy is based on a "suicide" gene introduced in tumor cells. These approach results now in phase 1 protocol.

Recent studies have shown that experimental tumors could be treated more efficiently with ionizing radiation if genetic material was transfered into tumor cells. Several approaches have been reported, and among them, the first one consisted of increasing the apoptotic response to radiation by modulating genes involved in the regulation of the apoptotic pathway. Indeed the modulation of p53 and bcl-2 gene expression has recently been used successfully in several experimental models to increase the apoptotic death after radiation. A second approach consisted of taking advantage of the conditional expression of some genes after exposure to ionizing radiation. Indeed, some genes exhibit a radio-inducible promoter which can be combined to a gene, able to enhance or decrease the biological effect of radiation. The irradiation of such a transgene under the control of a radio-inducible promoter can lead to a second biological effect, concomitant to the irradiation, as reported for the TNF alpha under the control of the EGR (early growth response) promoter. A third approach consisted of enhancing the effect of radiation induced tumor cell death by the expression of a suicide gene in these cells, as suggested recently for the HSV-tk (herpes virus thymidine kinase gene). These preliminary results obtained in experimental models appear to be very promising and might improve the efficacy and specificity of radiation therapy in a not too distant future.

Cytogenetic analysis of leukemic cells has been shown to be a mandatory part of the diagnosis of malignant hemopathies. Recurring abnormalities may be divided into those exclusively found in myeloid disorders, those associated with lymphoid diseases and those detected in both types of hemopathy. Several of the common defects are characteristic of specific FAB types or subtypes and associated with clinico-pathologic manifestations. Cytogenetic abnormalities have served to identify relatively homogenous subsets of malignant hemopathies. In view of the significant progress realized in the treatment of malignant hemopathies, the assessment of prognostic factors is particularly important for therapeutic decision making. The chromosome status at diagnosis has proven to be a major prognostic indicator for survival and outcome in individual patients. This article will focus on the diagnostic and prognostic significance of the karyotype in de novo acute leukemia and primary myelodysplastic syndromes.

Human tumors carry antigens that are recognized by the patients' cytolytic T lymphocytes. An important group of antigens is coded by the MAGE family of genes. These antigens are expressed in a significant proportion of tumors of numerous histological types but not in normal tissues. Clinical trials are underway in an attempt to immunize patients suffering from metastatic melanomas using peptides coded by the MAGE genes. Regressions have been observed in 5 of the 17 immunized patients.

Flat adenomas can be dysplastic from onset, whereas for polyps the risk of malignant transformation increases over time and with the size of the polyp. A dominant autosomal syndrome characterized by the development of flat adenomas has been reported. In a retrospective study of operative specimens from high-risk patients who had surgery for colorectal cancer, the author found that flat adenomas, which had been overlooked at initial evaluation, were a potentially useful phenotype. The mucosa adjacent to the flat adenomas showed hyperplasia and increased proliferation reminiscent of the morphologic abnormalities in aberrant crypts described by Pretlow; the latter have been found to occur rapidly in rats exposed to carcinogens and have also been demonstrated in patients at high risk for colon cancer. Aberrant crypt abnormalities and flat adenomas may be premalignant lesions.

Multiple endocrine neoplasia type 2 (MEN 2) is a cancer syndrome which comprises three related disorders, MEN type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC), MEN 2A is characterized by the association of MTC, a tumour arising from thyroid C-cells, pheochromocytoma and parathyroid hyperplasia. In addition to the thyroid cancer, MEN 2B associates pheochromocytoma, mucosal neuromas, ganglioneuromatosis of the digestive tract and skeletal abnormalities. In FMTC, the MTC is the sole clinical manifestation. MEN 2 is a dominantly inherited neural crest disorder caused by germline mutations of the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase, which displays a cadherin-like domain and a cysteine rich motif in its extracellular part. Missense mutations at one of five cysteines clustered in the extra-cytoplasmic domain of RET have been identified in the majority of the MEN 2A families and in two-thirds of FMTC. A single point mutation leading to the replacement of a methionine by a threonine within the tyrosine kinase domain has been detected in almost all cases of MEN 2B. We have screened 170 french MEN 2 families and a germline mutations in the RET gene have been identified in 92% of cases. Moreover, we confirmed the significant correlation between the nature, the position of the RET mutations and the clinical phenotype. The accurate identification by DNA testing of individual predisposed to MEN 2 suggests new protocols of treatment. Thyroidectomy as early as 6 years of age in individuals with MEN 2 mutations has been recently advocated by clinicians. We further provide evidence that MEN 2A and MEN 2B mutations convert the RET proto-oncogene in a dominantly-acting transforming gene due to the ligand-independent constitutive activation of the tyrosine kinase. Finally, we have constructed transgenic mice carrying the RET gene carrying a MEN 2A mutation fused to the calcitonin gene related peptide/calcitonin promoter. Animals of three independent transgenic lines developed C-cell hyperplasia and subsequently MTC with a complete penetrance. Taken together, these findings indicate that MEN 2A form of RET is oncogenic in thyroid C-cells, and suggest that these transgenic animals should prove a valuable model for hereditary MTC. Future work should yield insights in the signaling pathways subverted by the RET-MEN 2 proteins.

46 XY pure gonad dysgenesia, also known as Swyer syndrome, is a disorder of sexual differentiation. The patients are phenotypic females with a 46 XY karyotype and hypoplastic gonads without germ cells. They present most often with primary amenorrhea. The study of this abnormality in testicular differentiation contributed to the identification of the gene SRY, testis determining factor. To date, 20% of 46 XY pure gonad dysgenesia are explained by a mutation or a deletion in SRY. In 80%, SRY is apparently normal. The risk of gonadal neoplasia is high, dictating early prophylactic removal of these dysgenetic gonads. Gonadoblastoma and dysgerminoma are the most frequently reported malignancies. Because of the possible inheritance of XY gonad dysgenesia all family members should undergo a thorough screening.

Bovine thyroglobulin gene upstream regulatory sequences were used as a tissue specific promoter in order to direct the expression of different genes specifically to the thyroid gland. Transgenic models of thyroid diseases have been generated, by directing the expression of specific oncogenes to the thyroid cell. In one of these models (TgAgT), the sv40 large T antigen promoted the development of an aggressive undifferentiated tumor mimicking the phenotype of the human anaplastic carcinoma. In the second model (TgA2aR), the expression of the adenosine A2 alpha receptor, acting as a constitutive activator of adenylyl cyclase, resulted in the development of a hyperfunctioning goiter, and in old animals to the formation of malignant foci. Transgenic lines expressing the E6 oncogenic (TgE6) from type 16 human papillomavirus appeared to be asymptomatic. In contrast, the thyroid cells of mice expressing E7 oncogene divide very rapidly, but remain differentiated, resulting in the development of huge colloid goiters. Signs of malignancy appear late in the development. The molecular properties of E6 and E7 oncogenes are to bind, and inactivatc, the tumor suppressor gene producers p53 (E6), or RB (E7). Our transgenic models indicate that the RB protein (and/or related proteins) are essential factors in the negative control of thyroid cell proliferation. On the contrary, inactivation of p53 seems to play a minor role, at least in the early steps of tumor formation. In the last model (Tg alpha 1B), the expression of a mutant of the alpha 1B adrenergic receptor reported to activate both CAMP and sigma P3-CA-cascades, resulted in growth stimulation, hyperfunction, cell degeneracy attributed to the overproduction of free radicals and malignancy.

To analyze the association between colorectal cancer positive family history and screening practices.

Amongst family members at risk of developing familial adenomatous polyposis (FAP) to distinguish between those who are affected by the disease and those who are not, in order to provide optimal treatment to those requiring it whilst excluding those without the disease from the endoscopic surveillance programme.