The molecular characterization of the recurrent chromosomal translocations associated with T-cell prolymphocytic leukemia recently led to the identification of two putative oncogenes: TCL1 located on chromosome 14q32.1, and MTCP1 located on chromosome Xq28. These genes code for two homologous small cytoplasmic proteins lacking similarity with other known proteins. Uncovering the function of these proteins will be the next step toward an understanding of pathogenesis of the T-cell prolymphocytic leukemia.

This paper reports the first karyological study of a gill neoplasia in the bivalve Macoma balthica from the Bay of Gdansk (Poland). Chromosomes were studied with an air-drying technique from gill tissue. Out of 47 specimens studied, 34 showed normal cells and a variable number of mitotic metaphases with a normal diploid chromosome number of 2n = 38, 6 had hypertrophied nuclei and a high number of mitoses with 70 to 98 chromosomes, and 7 specimens showed intermediate features. The karyotype of normal metaphases included 11 metacentric, 2 submetacentric and 6 subtelocentric chromosome pairs. The karyotype of abnormal metaphases, i.e. with a high number of chromosomes, revealed chromosomal aberrations inferring neoplastic disorders such as: different number of metacentric, submetacentric, subtelocentric and telocentric chromosome pairs than in the normal karyotype, increase of chromosome pairs especially in the small and medium-sized chromosomes, irregular monosomy and occurrence of microchromosomes. According to neoplasias recorded in bivalves species, the prevalence observed in this neoplasia is relatively high. As Macoma balthica inhabits the polluted Bay of Gdansk, the effects of environmental parameters should be elucidated.

Human papillomaviruses (HPV) have been implicated in the pathogenesis of human squamous cell carcinoma, specially of cervical carcinomas. In previous studies concerning primary lung cancer, DNA of HPV subtypes was detected by in situ hybridization or polymerase chain reaction (PCR), up to 30% of the cases, namely in squamous cell carcinomas. A series of 31 frozen biopsies of lung carcinomas (surgical biopsies or through fiber optic bronchoscopy) were examined for the presence of HPV DNA by nested PCR. Primers for the two steps were type-specific primers (6/11-16 and 18; kit Amplicis-HPV) for the transforming region of HPV. HPV-DNA was found in five tumors: in two of 18 cases of squamous cell carcinoma (11%), in one of four cases of adenocarcinoma, in one of six cases of small cell carcinomas and in the unic case of neuro-endocrin carcinoma. No case of the two large cell undifferentiated carcinomas was positive. There were three cases of HPV 6/11, one case of HPV 16, and one sample positive for HPV 6/11 and HPV 18. No morphologic changes consistent with HPV lesions were observed. The frequency of 11% among the squamous cell carcinomas is near those found by previous studies (9 to 20% for HPV 6-11-16-18). For the first time, HPVs have been detected in neuro-endocrin tumors, and this have to be confirmed by studies of many more cases. So HPV might play a role as promoter in carcinogenesis of any types of lung carcinoma, although at a low frequency.

Multiple endocrine neoplasia type 1 (MEN 1) is an inherited disorder characterised by slow progressing tumors of the parathyroids, of the endocrine pancreas and of the anterior pituitary. A genetic locus predisposing to this disease has been localised on chromosome 11. Predictive diagnosis of carriers of the defective gene is possible in families using genetic markers at this locus. However, this analysis presupposes a precise identification of affected subjects. Moreover, expression of the disease may vary from one family to the other. The aim of the present study was to define the typical clinical features of the syndrom.

Splenic lymphoma with villous lymphocytes (SLVL) is a low grade lymphoproliferation characterized by a massive splenomegaly, an absence of lymphadenopathy and the presence in the peripheral blood of atypical B-lymphocytes with hairy-cell appearance. We have studied the morphological, immunological and molecular characteristics of 3 cases of SLVL. SLVL presented on blood smears characteristic irregularities of the plasma membrane consisting in thin and short villi unevenly distributed. The main phenotype was CD5-, CD11c+, and CD25-, but individual SLVL cases can not be identified by using immunohistochemical criteria alone. Clonal rearrangements of the immunoglobulin heavy chain gene were found in all 3 cases and in one case presented a bcl2-JH rearrangement. SLVL are clonal B-cell lymphoproliferations and can be associated with t(14; 18) translocation.

Genetic consultations allow to identify families in which an hereditary predisposition to cancer is transmitted. In most cases the gene involved can be studied leading to identification of families members carrying or not the mutation conferring the cancer risk. In this case, cancer risk is more accurately explained and measures, adjusted to the risk, were proposed for early screening of the disease. Capacities to characterize an inherited mutation of the susceptibility gene vary according to our knowledge of the gene, its structure, its function, the kind of mutation(s) and also, the available techniques. The purpose of this paper is to describe the most frequently used techniques for direct or indirect molecular diagnosis of cancer predisposition and to specify, for each of them, the situations where its use seem the fittest. The example of breast cancer hereditary predisposition, where multiple susceptibility genes were identified and other are still unknown, illustrates the various degree of diagnosis that can be proposed and the strategy techniques used according to the gene.

Search for mutations of BRCA1 in women at hereditary risk for cancer is now possible. We asked the female gynaecologists of our county (north of France) their opinion about the search of a mutation of BRCA1 if they had a familial risk of breast cancer. Our aim was to obtain the opinion of informed women about their willingness to do the test for themselves and about the consequences they should accept. One hundred and eighty-three women received a questionnaire by post. The response rate was 56.3%. Twenty-four percent of the responders had a first degree relative with breast cancer. Most of the responders (87.4%; IC 95%: 81-93.8) would ask for the search of a mutation of BRCA1. The percentage of women who would accept the test is smaller for the women who have a first degree relative with breast cancer (72.0% vs 92.3%; P = 0.02). The reasons given to do the test were a better screening or prevention (69.7%) and the knowledge of a personal risk (49.4%). For breast cancer, 93.2% (95% CI: 88.4-98) would accept a screening protocol, 30.1% (CI: 21.3-38.9) would accept a prophylactic bilateral mastectomy. For ovarian cancer, 93.2% (CI: 88.4-98) would accept the screening, 52.4% (CI: 42.8-62) would accept a prophylactic ovariectomy. In conclusion, most of the informed women would ask for the test and the surgical options for reducing the risk of cancer are not absolutely rejected. Of course, only future studies will state precisely the choice of truly implicated women.

Retinoblastoma, a tumor of the immature retina concerns babies and young infants in particular. They make up for 14% of malignomas in the first years of life. There are two types of retinoblastoma: In the first two alleles of the gene Rb1 must be inactivated sequentially in the same retinoblast cell until this may escape control. In this case the retinoblastoma is always unilateral and unifocal. This is explained by the lower frequency of two mutations in one retinoblast. The other type, however, is inherited: One allele Rb1 is inactivated in all cells of the organism by mutation. The probability that a second mutation arrives in different retinoblasts is thus high. In this case bilateral multifocal tumors develop. Characterization of the Rb1 gene has permitted identification or at least determination of a haplotype in persons at risk. This knowledge is decisive for early recognition of babies at risk and for genetic counselling.

Familial adenomatous polyposis (FAP) is an autosomal dominant disease characterized by the development of numerous adenomatous polyps in the colon and rectum with diverse extracolonic manifestations. Recent genetic advances have lead to the sequencing of the FAP gene, with important implications for screening, diagnosis and follow-up. Appropriate management of probands and at-risk patients is of the utmost importance, as untreated carriers will develop colorectal cancer. Identification of FAP families and tracing of pedigrees represent the most important steps. To this end registries are essential, allowing a comprehensive multidisciplinary approach. They have justified their place by decreasing related morbidity and mortality. An overview and discussion of clinical features and management are presented.

Each year 3500 new cases of colorectal cancer (13% of total cancer cases) are registered in Switzerland. A yet unknown proportion of these cancers is associated with recently discovered gene defects in one of at Peast 4 genes participating together in an essential process. The function of these genes aims at the correction of certain erroneous hereditary informations that may occur when bases are not or mis-aligned. Mutations leading to anomalies in the expression of one of these genes favour strongly the development of certain early carcinomas, because they lead to an accelerated accumulation of further mutations expected to trigger carcinogenesis. It is estimated that about 2-3/1000 of the population carries a gene error typically manifested as the so called Lynch Syndrome, that concerns not only the colon but also the uterus, ovaries, the urogenital tract and diverse parts of the gastro-intestinal tract. The first observation which led the identification of these genes was a genetic instability within tumor cells showing a distinctly increased mutation rate in many different locations of the genome. Molecular identification of a factor predisposing to malignancy in one of these repair genes permits on one hand to abolish unnecessary investigations in members of families at risk that could be identified as non-carriers of this incriminating mutation and on the other hand to concentrate medical attention on carriers.

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal, dominantly inherited disease leading to a marked increase in cancer susceptibility, notably colorectal cancer, affecting up to one in 400 individuals in the Western world. Four genes responsible for the majority of cases have been identified. Colorectal cancer in affected people tends to be right sided, occur at an earlier age, and there is a propensity for synchronous or metachronous lesions. Extra-colonic tumours may occur with an elevated frequency, most importantly cancer of the endometrium, but also stomach, hepatobiliary system, small bowel, proximal ureter and renal pelvis, and ovary. On account of these features, management guidelines for members of HNPCC kindreds require modification from those generally advised for patients with sporadic tumours. The cardinal feature for the identification of affected families is the family history. All clinicians have a duty to identify such patients under their care as appropriate screening and surgery should lead to an improved prognosis for such patients and their families.

Recently, genetic analyses in high risk families with several members suffering of breast and/or ovarian carcinoma led to the discovery of two genes, called BRCA1 and BRCA2, clearly responsible for hereditary predisposition of breast carcinoma. Another gene, p53, was also shown to be involved in hereditary predisposition of breast and other tumors in the setting of Li-Fraumeni syndrome. It is very important that women at risk could be seen by a specialized team for genetic counselling and explanation of advances and limits of molecular genetics. Such a team should be multidisciplinary in order to cover genetic, oncological, social, psychological and economical aspects of hereditary cancer predisposition. Prevention interventions and early detection methods are still investigational and definitely need to be performed in the setting of protocols in order to better evaluate their long term efficacy.

This presentation summarizes hereditary cancers of the ovary and of the endometrium, describes risks of women belonging to a family at risk and proposes a therapeutic strategy.

Some aspects of genetic counselling in cases with familial cancers is illustrated by use of 4 typical observations. By exact diagnosis and extended genealogic analysis the risk of consanguineous relatives may be estimated, if inheritance and genetic peculiarities of the particular disease are known. Predictive and presymptomatic testing should only be undertaken after thorough counselling. It should anyway be restricted to cases where preventive or curative measures are available.

Oncogenes and anti-oncogenes form two families of genes. If abnormal both may induce malignancies. They are distinguished, however, by two components. Oncogenes play a certain role in a given period of development (mainly during organogenesis). As soon as function has been completed they are inactivated. Aberrant reactivation even of one allele may induce tumors in different tissues independent of age. Anti-oncogenes on the other hand protect the organism, functioning mainly at the level of cell cycle regulation. Because one allele is sufficient for sustaining of adequate function both alleles of the anti-oncogene must be destroyed before tumor development is possible. Such a tumor will be tissue- and age-specific.

Thirty-six French centres are involved in an evaluation of the techniques used for MDR phenotype measurement. Until now, 14 samples of various kinds of leukemia (mainly acute myelogenous leukemia) and three cell lines with different levels of resistance were sent by one centre and tested. MRK16 antibody was used for flow cytometry and immunocytochemistry, RNA was measured by RT-PCR, rhodamine or anthracyclin efflux were tested for functional assay. Wide discrepancies were observed in the results, mainly with flow cytometry, specially for the samples with a probable low level of MDR1 expression. The importance of histogram interpretation was documented by the comparative analysis of results obtained on cells already marked with MRK16, fixed and sent to all centers. The use of the ratio of the mean of fluorescence, instead of percentage, should help for standardization. The use of only one control RNA (used at different dilutions) for standardisation of RT-PCR could help in decreasing the discrepancies observed. The mean of fluorescence should also be used for expressing the rhodamine cell content.

The results obtained from 12 laboratories, dealing with six identical malignant solid tumors, assessing MDR1 phenotype using molecular techniques and immunohistochemistry have been compared. Moreover, comparisons between results of MDR1 gene expression, quantified by RT-PCR or Northern blot analysis from 10 RNA and 10 cDNA samples, were also compared between eight laboratories. Results concerning solid tumors show frequent discrepancies between the results obtained by immunohistochemistry and molecular biology techniques. Moreover, inter-laboratory discrepancies concerning immunohistochemistry techniques are observed, suggesting that the interpretation of staining is critical. Results of RT-PCR and Northern blot using RNA and cDNA show that discrepancies are less frequent than those observed using immunohistochemistry. However, Northern blot is not sensitive enough to be used in routine. The problems encountered using RT-PCR are the following: positivity threshold level, reproducibility and risks of cross-contamination.

EB Lewis, C Nusslein-Volhard and E Wieschaus were the winners of the Nobel prize in 1995 for the discovery of genes controling the embryonic development in drosophila. Drosophila development is dependent on sequential activities of three types of genes: the maternal genes, the segmentation genes, and the homeotic genes which are responsible for the segment identity and finally for the building of the body. Mutations of these genes are spectacular because they affect the body structure formed from individual segments. Therefore, the molecular processes regulating the development of inferior organisms such as yeast or more complex as the vertebrates were elucidated by these three researchers. These early biological mechanisms regulate the cell life through interactions with neighbouring cells. We speculate that any alteration of these processes might be implicated in cancer. Understanding of these molecular mechanisms which control cell interactions in cancer constitutes a basis for definition of new prognostic markers and putatively novel therapeutic approaches.

Molecular studies on pituitary adenomas support a major role of molecular alterations in the pathogenesis of pituitary adenomas. Nevertheless, alterations in the neuro-hormonal control of the pituitary could also be involved in pituitary tumors formation. The finding that most pituitary adenomas are monoclonal has stimulated a search for somatic mutations. For instance, activating mutations of the Gs protein, leading to constitutive stimulation of the cAMP pathway, have been found in a subset of GH-secreting adenomas. But GHRH (growth hormone-releasing hormone) tumoral hypersecretion also stimulates the cAMP pathway and causes acromegaly. Pituitary tumor formation might result from accumulation of several alterations that would determine the tumoral phenotype. The majority of these alterations remains to be found.