A brief description of the results obtained by cytogenetic analyses of cancer cells from colorectal adenocarcinomas is reported. Two distinct patterns of chromosomal anomalies are observed. The major one, called "monosomic type", because many chromosomes losses exist, is characterised by the losses or deletions of the following chromosomes 18, 17 (short arm = p), 1p, 4, 14, 5 (long arm = q) and 21. It frequently evolves towards polyploidy, by duplication of all remaining chromosomes. The minor one, called "trisomic type", is characterised by the gain of several chromosomes: 7, 12, X, 5 and 8. The chromosomal anomalies observed seem to have no topological relationships with oncogenes, and other interpretations for their occurrence were investigated. The numerous and frequent deletions of some chromosomes, like 17p and 18, may indicate the involvement of recessive genes, like in the anti-oncogene system. In addition, it is observed that most deletions involve genes for "de novo" pathways whereas gains involve genes for salvage pathways of the synthesis of nucleotides. A correlated cytogenetic and enzymologic study was thus developed, and the first results show that the chromosomal pattern may well indicate the metabolic deviations. Monosomic type tumors have, on the average, a relatively low "de novo" and a high salvage pathways, and trisomic type tumors a high "de novo" and salvage pathways. Since chemotherapy is principally orientated against "de novo" pathways of the synthesis of nucleotides, these results may help to understand the difficulties of chemotherapy in colorectal cancers and perhaps to adapt it better.

Two new cases of Cowden's disease observed in two young sisters are reported. The diagnosis was based on the clinical observation of oral mucosa lesions (gingival hyperplasia, papillomatosis, scrotal tongue). In one case, visceral manifestations in childhood were observed. Cowden's disease is a familial affection (autosomal dominant trait) characterized by association of oral mucosa and skin lesions and of multiple hamartomas involving glandular tissues. Clinical and familial history investigations are justified by the high risk of malignant tumors (breast carcinoma).

Isolated communities offer a unique opportunity for the study of biological and social consequences of consanguinity and migration. The studies of genetic polymorphisms have contributed greatly, not only to knowledge of the genetic constitution of a given individual and population, but also to clarify either relationship between structure and function of polymorphic traits or the susceptibility to multifactorial diseases, in which interaction between the gene and environment cannot be ignored. For over 25 years, we have investigated the effect of consanguinity and genetic polymorphisms in 9 isolated communities in Western Japan. We reported here different values of gene frequency for each polymorphic trait, compared with the neighboring communities and described how we applied these data to clarification of the genetic constitution of isolated communities as well as of genetic susceptibility to some diseases.

The c-myb gene was studied in 112 breast cancers. c-myb and estrogen receptor (ER) transcripts were found in 78 (70%) and 71 (63%) cancers respectively. Of these 71 ER positive cancers, 64 (90%) contained c-myb transcripts and of the 41 ER negative cancers, 27 (66%) did not contain c-myb mRNA. Our data show that c-myb transcripts are strongly associated with ER and progesterone receptors (p less than 10(-4) status in breast cancer. Thus the c-myb expression could be associated with breast cancers of better prognosis and its analysis could allow a better characterization of new subsets of hormono-dependent cancers responding more efficiently to hormonotherapy.

Ten genes responsible for the increase of specific tumor incidence in affected families have been localized on the human genetic map. This knowledge not only provides the mean of a precise genetic counselling but also opens a way for further investigating the genetic mechanisms of these disorders. Usually, it is admitted that dominantly inherited familial predisposition to tumors is due to a defective tumor suppressor gene. This hypothesis is almost certain for familial retinoblastoma, highly probable for hereditary nephroblastoma and possible for neurofibromatosis type II. In contrast, the gene for familial polyposis coli shows some characteristics of activated oncogenes.

10% of patients with medullary thyroid carcinoma have a family history of this cancer. The genetic nature is much more marked in the associations known by the name of multiple endocrine neoplasms (MEN) type II. Type IIa is compatible with autosomal dominant inheritance. The clinical symptoms may be revealed later, but the response of calcitonin to pentagastrin should allow the diagnosis of all carriers of the gene before the age of 35 years. The incomplete nature of clinical penetrance (probably 80%) may lead to errors of omission in the screening. The disease appears to be less aggressive in certain lines, without any explanation at the present time. The locus of MEN is probably on chromosome 10, in the centromere region or nearby on the long arm. The mechanism of tumourigenesis has not yet been elucidated. Hopefully, in the near future, reliable markers for the identification of children at risk will be available together with an understanding of the genetic heterogeneity of the disease.

In a large kindred with multiple endocrine neoplasia type 2a (MEN 2a) (137 members, 5 generations), bilateral thyroid medullary carcinoma was found in all affected members. Pheochromocytoma was present in 59% of the cases, and was responsible at least for 4 out the 5 deaths related to MEN 2a. Hyperparathyroidism was less frequent (41%). Family screening leads to a reduction in age for diagnosis and to an improvement in the prevalence of complete healing after surgery. Linkage between HLA loci and a dominant gene for MEN 2a was investigated in this kindred. Lod scores for recombination fraction were all negative (-0.47 for a recombination fraction of 0.05). These results comfort the lack of linkage between MEN 2a and the HLA complex.

The majority (1013) of cases of medullary carcinoma of the thyroid observed in France in the last twenty years have been registered in a national file. Once overcome the difficulty of diagnosing the index case, all first degree parents at least should undergo a pentagastrin stimulation test and calcitonin estimation. Though such a policy involves difficulties of several types, it has resulted in the detection of 203 cases belonging to 61 families. 29 families suffered only from isolated MCT; in the 32 other families this cancer was a part of polyendocrinopathies of type 2a (28 cases) or type 2b (4 cases). The tumour was apparently of the sporadic type in 208 subjects. In 602 other cases the data were insufficient for a correct classification. An epidemiological enquiry of the disease is in progress since 1986. Though the number of complete files analysed is still insufficient, this study will be essential in understanding the natural history of the disease, the causes of its heterogeneity and in deducing eventually preventive measures even if in meantime a genetic marker is available.

Proto-oncogenes, which have been widely implicated in the pathogenesis of malignant human tumors, frequently demonstrate restriction fragment length polymorphism (RFLP). Population studies of such restriction alleles is of potential interest for genetic analysis of cancer susceptibility. Some of the initial date of Krontiris et al (1985) showing a significant increase of rare c-ha-ras-l alleles in individuals with tumors, have been confirmed in certain types of cancer (breast cancer, lung adenocarcinoma), whereas others have been refuted (myelodysplasia, melanoma, colon adenocarcinoma). Other significant associations have been found between other proto-oncogene RLFPs and tumors (c-mos and breast cancer, c-raf and non Hodgkins lymphoma, L-myc and lung carcinoma metastasis). Although they are controversial, these studies should be extended, in order to determine whether the presence of certain alleles is a contributing factor in the development of certain tumors.

ACTH is produced by proteolysis of a polypeptide precursor, proopiomelanocortin (or POMC). Various POMC-derived peptides are cosecreted with ACTH. Analysis of the ACTH--and its "satellite" peptides--molecular forms establishes the POMC "maturation profile" in different tissues. This profile is identical in normal and tumoral pituitaries (Cushing's disease and/or Nelson's syndrome). It is often altered in non-pituitary tumors responsible for the ectopic ACTH syndrome: abnormal peptides may be generated (CLIP h beta MSH5-22) which can be detected in blood. Analysis of POMC gene transcription in pituitary tumors shows no abnormality. In some non-pituitary tumors the activation of upstream promoters up to 369 nucleotides from the normal (pituitary) transcription initiation site can be shown. In normal non-pituitary tissues a third type of transcription is observed generating a short and probably non-functional messenger RNA limited to a portion of the gene non-coding region.

Progress achieved in the understanding of small cell lung cancer (SCLC) include: the establishment and characterization of cell lines with the identification of a variant type with poor prognosis; the use of non-specific biochemical markers such as neuron specific enolase (NSE) and calcitonin; the generation of monoclonal antibodies (MoAbs) directed against SCLC antigens; growth factors including GRP and IGF. GRP or human bombesin produced by the tumor cells favours their own growths; in cytogenetics, with the observation of a characteristic chromosomal abnormality: the deletion of the short arm of chromosome 3 (3p 14-23). The region deleted is currently under study to identify the genes potentially involved in the oncogenesis of SCLC. the activation of several oncogenes: C-myc, N-myc, L-myc, Myb, Raf-1. The amplification of C-myc favors the tumor cell progression and is related to a bad prognosis. This biological approach has confirmed the neuroendocrine origin of these tumor cells (as a result of protein studies of the cytoskeleton and of MoAbs); it has allowed the use of tumor markers in the diagnosis and work-up of SCLC and the consideration of new therapeutic approaches. Current studies concern the deletion of 3p- and the integration of the cytogenetic data, growth factors and oncogenes in a coherent model of the genesis of SCLC.

Preliminary results of genetic and epidemiological study of Wilms' tumor in France are given in this paper. The higher age at diagnosis in unilateral than in bilateral cases supports the bimutational theory of Knudson. The excess of cancer deaths found in relatives of patients might be due to genetic non specific factors of susceptibility to cancer.

In a family including patients suffering from autoimmune disease (2 propositi: pernicious anemia and Graves' disease, pernicious anemia and autoimmune thyroiditis), we have determined common autoantibodies and tissue antigens (HLA) in 47 patients (26 males and 21 females) from 2 generations. In this family, we have found 4 cases of pernicious anemia, 5 cases of thyroid disease (2 Graves' disease), 3 women with repetitive abortions and 2 cases of melanoma. Patients with autoantibodies, often asymptomatic, are abnormally numerous (44% in generation II, 16% in generation III). A correlation with haplotype A1B8DR3 was found only for Graves' disease. Likelihood of forming autoantibodies appears to be of multifactorial origin. Its mode of transmission remains unknown.

A turkish family with three sibs (including twins) affected by the lethal multiple syndrome is reported.

The authors report the case of a 42-year old woman who developed chronic myelocytic leukemia with Philadelphia chromosome followed, 21 months later, by malignant follicular lymphoma with small cleaved cells and giant cells. This case is comparable to the other associations of acute or chronic myelocytic and lymphocytic blood diseases previously published. Several pathogenic theories are reviewed. They involve chemotherapy with alkylating drugs (but the diagnosis is sometimes simultaneous), cellular oncogens or, more probably, a clonal abnormality of the stem cell sequentially or concomitantly expressed in the cells of both lineages; unfortunately, in the absence of Philadelphia chromosome this theory has not yet been demonstrated on lymphoma cells.