Recurrent allelic losses on chromosome 22q have been reported in colorectal cancer, distal to the NF2 gene, suggesting that another tumor suppressor gene might be involved. We report here the typing of 256 sporadic colorectal tumors and 18 colonic cancer cell lines using a set of chromosome 22 polymorphisms, ranging from 20 to 45. A panel of somatic cell hybrids, that allows to distinguish 11 bins in the 22q13 region, was used to localize 19 of the 45 selected markers and the putative tumor suppressor gene BZRP. Allelic-loss was observed in 43% of tumors. The minimal region of deletion that could be determined, telomeric to locus D22S270, refines significantly the position of the gene. The localization of the BZRP gene in this region led to a systematic screening for somatic point mutation. Direct sequencing of its coding sequence in 36 tumors hemizygous for chromosome 22 allowed the identification of three polymorphisms but failed to detect somatic mutation.

Several transactivating factors specifically involved in the differentiation and proliferation of anterior pituitary cell types have been recently identified. Among them Pit-1 a member of the POU-domain transcription factors family is specific of anterior pituitary cells, and was initially identified and cloned as a transactivator of the GH and PRL genes and as a regulator of the TSH beta gene. Pit-1 play a key role during embryogenesis in the differentiation and proliferation of somatotrophs, lactotrophs and thyreotrophs. The importance of Pit-1 as a regulator in the anterior pituitary development has been further demonstrated by naturally occurring mutations or delections in dwarf mouse strains. In the Snell and Jackson dwarf mice, the levels of Pit-1 gene expression are low or undetectable, GH, PRL and TSH beta gene expression are absent and lactotrophs, somatotrophs, and threotrophs fail to proliferate. Furthermore Pit-1 carries out similar functions in humans. This is supported by the fact that children with mutations of the Pit-1 gene present with a congenital combined GH, PRL and TSH deficiency analogous to the phenotype of the Snell and Jackson dwarf mice. In children who were born to healthy consanguinous parents and present such combined deficiencies we recently reported a Pit-1 mutation causing a transition from a Phe to a Cys in a region of the protein known to be involved in DNA binding. Pit-1 transcripts identical in size and sequence to those observed in normal pituitary were described in human GH, PRL and TSH secreting pituitary adenomas. The Pit-1 beta isoform, raised through alternative splicing of exon 2 of the Pit-1 gene, is a more potent inducer of GH transcription than the major Pit-1 form. However no difference in the level of expression of the different Pit-1 isoforms was observed between tumors identified as pure GH or PRL producing tumors. The results support the existence of other transcription factors interacting with Pit-1 to coordinately regulate the activity of the GH and PRL promotors in a cell specific manner. In contrast, variable Pit-1 expression was observed in prolactinomas, according to their sensitivity to bromocriptine treatment. A highly significant correlation was indeed evidenced between the D2 receptors mRNA and the Pit-1 mRNA levels. These results raise the possibility that Pit-1 may either directly or indirectly affect the transcription of the D2 dopaminergic receptor gene. In fact, receptors for other hypothalamic neurohormones such a GHRH and somatostatin are known to be potential Pit-1 target genes. Such mechanisms could be implicated in the differentiation and proliferation of lactotrophs and somatotrophs.

Genetic events involved in breast tumor formation are described. Abnormalities known point to determine the genes which participate in tumorigenesis. Mechanisms involved should be oncogene activation, tumor suppressor gene inactivation, abnormal protein expression. Multiple genetic alterations are probably necessary for a normal tissue to become malignant. Most of these genetic alterations seem to be somatic. Only 1 or 2 steps can be inherited and in familial cancer only (5% of breast cancers). Characterization of altered genes at somatic level during carcinogenesis will allow progress in the understanding of the molecular mechanisms involved and in the use these genetic markers in clinical oncology.

Tamoxifen is the most currently used antiestrogen in the endocrine treatment of breast cancer. However, despite a small proportion of estrogen receptor positive tumors presenting de novo resistance to treatment, numerous tumors develop acquired resistance after a first phase of response. Many mechanisms have been proposed, but none could be identified as a real explanation of these phenomena of resistance. The hypotheses suggested are related to the series of events implied in the transduction of the signal following the ligand binding to estrogen receptor and concerning several levels: (1) loss or mutation of the estrogen receptor; (2) modification in estrogen receptor associated parameters; (3) alteration in the estrogen response element; (4) high levels of antiestrogen binding sites; (5) alteration of metabolism or availability of tamoxifen. The tamoxifen resistance certainly concerns several of these mechanism. Therefore, it is necessary to go on studying these mechanisms and to elucidate the connections existing between all of them.

Polymorphic epithelial mucin (PEM), encoded by the MUC1 gene, is present at the apical surface of glandular epithelial cells. It is both overexpressed and aberrantly glycosylated in the majority of breast tumors, resulting in an antigenically distinct molecule and a potential target for immunotherapy trials. This transmembrane protein is cleaved into the circulation where it is detectable as a tumour marker (CA15.3) by a variety of antibodies, allowing for early detection of recurrences as well as evaluation of treatment efficacy. We shall review here the molecular structure of this protein at the basis for its immunogenicity and discuss preclinical and clinical trials in progress using immunogens based on MUC1. We shall also briefly review the altered immune reactivity in cancer patients.

The BRCA1 gene modification is responsible for an autosomal dominant syndrome of inherited early onset breast and/or ovarian cancer. This gene is estimated to account for almost half of inherited breast cancers and three quarters of inherited breast/ovarian cancers. This suggests that about 1 out of 500 women may carry BRCA1 mutation. The BRCA1 gene was isolated by positional cloning in 1994. More than 100 different mutations have been found in the germline of affected individuals. We looked by systematic sequencing at BRCA1 germline mutations in 36 patients treated at the Centre Oscar-Lambret for breast and/or ovarian cancer and that belonged to high risk families. We have found 24 mutations: 9 true mutations inducing modifications of the BRCA1 protein (BRCA1+), 5 mutations with unknown consequences on the BRCA1 protein and 10 mutations corresponding to polymorphisms that had been previously described. All the BRCA1+ cases had a HPG3 tumor. The median age of discovery and the receptor positivity percentage are lower in hereditary breast cancer than in the standard population of the breast cancers treated in our center. Consequently, BRCA1 mutations are associated to parameters thought to be of bad prognosis.

Glutathione S-transferases mu (GSTM) are dimeric cytosolic isoenzymes. They catalyze glutathione conjugation upon a large variety of electrophiles as carcinogens, trans-stilbene peroxide or benzo(a)pyrene. The gene GSTM1 is localized on chromosome 1p13, it has drawn attention because it is absent approximately in 50% of the white population. GSTM1 null genotype seems linked with susceptibility to cancers as lung, colon and bladder cancers. We have studied GSTM1 genotype from 373 primary breast tumours. The GSTM1 null genotype was found in 50% of the cases (185/373). The incidence study of GSTM1 copy number on clinical and biological variables displayed a significant difference (p < 0.01) of the GSTM1 genotype, showed by the tumour, according to the patient age at diagnosis. The patients younger than 55 years had a percentage more important of primary tumours (65%) with a copy number of GSTM1 gene, inferior or equal at one, compared to the patients older than 55 years (52%). The tumours, whose cathepsin D level was high, presented few copies of GSTM1 gene (p < 0.03). There was no other relationship, particularly, with tumour size, node status, histological type, hormonal receptors, pS2 cytosolic level GSTM1 gene seems protect the mammary gland from cancerogenesis with its detoxification role. This results had not, pointed out in breast cancer, yet.

Familial adenomatous polyposis may exhibit extracolonic tumors which include thyroid carcinoma. It has been recently suggested that thyroid carcinomas associated with familial adenomatous polyposis show distinct histologic features different from sporadic follicular or papillary thyroid carcinomas. We report a case of thyroid carcinoma in a young girl affected by familial adenomatous polyposis, whose thyroid tumor exhibited some of these features. This finding confirms the peculiar histologic phenotype of the thyroid carcinomas associated with familial adenomatous polyposis. Alterations of the APC gene responsible for familial adenomatous polyposis may play a role in the development of these thyroid cancers.

Two patient with familial cavernous angiomatosis presenting with long lasting variable epilepsy with a poor therapeutic response and variable neurologic impairments are presented here. One of the numerous cavernous angiomas was resected in one case. This last patient remains asymptomatic. Familial cerebral cavernous angiomas are often numerous and disseminated in the brain, therefore clinical manifestations are very polymorphous. Moreover the course of these lesions is variable. Therefore MRI should be performed to every patient presenting with poorly understood neurological symptoms, focal or generalized epileptic seizures or absence in order to look for potentially imputable brain lesions. A reliable genetic marker might be helpful for diagnosis of this disease with a variable penetrance and autosomal dominant inheritance. Then a neurosurgical treatment should be carefully discussed if lesions are accessible and medications are poorly efficient with recurrent neurologic impairments or epilepsy.

Although rare (10% of thyroid cancers), medullary thyroid cancer is remarkable by the presence of a specific biological marker; elevation of blood calcitonin. It allows its preoperative diagnosis and this extensive surgery which is the only efficient treatment. The possibility of hereditary form (30%) must always be kept in mind; they can now be detected by genetic screening since specific mutations on Ret gene have been recently discovered. Follow up and early treatment of at risk subjects in a family is therefore possible and permits definitive surgical cure.

Medullary thyroid carcinoma (MTC) is characterized by different clinical forms and a possible prolonged survival, despite presence of metastases. In the present study, we have studied the clinical and biological characteristics of 119 decreased MTC patients.

We report the case of 68-year-old woman with an adenocarcinoma of the right colon. The family history also suggested that she might also be at risk of ovarian or endometrial cancer. Thus despite the lack of gynecologic symptoms, abdominal hysterectomy and bilateral salpingo-oophorectomy was proposed at the time of the right colectomy endometrial carcinoma was discovered at surgery. This finding and the family pedigree were consistent with the diagnosis of familial Lynch II syndrome. Appropriate biomolecular analyses were undertaken. This case shows the importance of family history taking in patients with cancer. The surgeon should be aware of such situations and correlate indications and procedures with the genetic risk of the patients.

Gene therapy defines a new therapeutic avenue whose site of action is at the level of the gene itself; viral vectors (adenovirus, retrovirus, herpes virus) or non-viral (liposomes, plasmids) enable the transfer of a fraction of DNA (transgenic) to the target itself. In this review, we present recently acquired data on the mechanisms of oncogenesis and anti-tumor immunity which have enabled the application of several therapeutic strategies in oncology; the transfer of gene(s), coding for cytokines or for coactivation factors in order to develop active immunotherapy; the transfer of suicides genes; the transfer of multidrug resistance gene (MDR1); the transfer of tumor suppressor genes or of cDNA coding for antisense oligonucleotides in order to correct genomic anomalies which are responsible for the malign phenotype. The development of gene therapy demands the resolution of a number of technical difficulties such as vectorisation, targeting, and the expression of the stability of the trans-gene. Phase 1 trials in man have established the innocuity of certain vectors and have confirmed the expression of trans-genes (marker genes). Compared to monogenic hereditary diseases, the "molecular heterogenetic" of bronchial tumours, the consequence of the instability of the genome and the diversity of amplified oncogenes are a major difficulty. In addition, each one of these approaches prevents limiting factors: for example the exclusive targeting of malign cells is an indispensable pre-requisite for the transfer of suicide genes and in the same way the expression the tumour in antigens is the pre-requisite for the development of active immunotherapy. We report the overall results of applied trials for pulmonary carcinomas on murine models and present their applications which are underway in men.

The incidence of clinical prostate cancer varies across countries and ethnic groups. Genetic and epigenetic factors have been suggested as possible explanations to these variations, although no mesological factors with clearly significant effects have been identified. About 20% of patients with prostate cancer have a family history for this disease. Several studies have reported links between prostate cancer and breast cancer, suggesting that the same loci may predispose to both diseases. Identification of one or more inherited genes associated with an increased risk of prostate cancer in some families may be useful for identifying high-risk individuals. The value of this approach has been demonstrated in other familial cancers, such as colon and breast cancer. Current goals of research in this field are to localize the gene(s) that predispose to familial prostate cancer and to identify the molecular alterations related to tumor progression in sporadic and familial prostate cancer.