Onco-Suppressor Genes in Human Cancer

Abstract

The analysis of the molecular mechanisms governing multistep carcinogenesis became experimentally approachable since the identification and characterization in tumor cells of altered or activated versions of cellular genes (oncogenes) that normally control cell growth and differentiation. The activating mutations confer new properties to the oncogene products and should therefore be considered as gain of function mutations. In addition, the oncogenes appear to act as dominant genetic traits since they act also in the presence of the homologous wild-type allele. However, the concept of a dominance of the transformed phenotype has been challenged by early experiments with somatic cell hybrids which showed that the fusion of normal and malignant cells may suppress the tumorigenic phenotype. The suppression or reversion of the malignant phenotype by the introduction of a normal chromosome into a tumor cell line has lent support to the idea that a family of cellular genes are coding for factors capable to interact with the cell-growth control machinery. These genes seem to reconstitute the normal control of cell growth even in the presence of an activated oncogene. In addition, a two-mutation model has been proposed to explain the epidemiological and clinical features of childhood cancers. According to the model, the development of these malignancies can be caused by the loss or inactivation of both alleles of cellular genes, as suggested by the somatic cell hybrid experiments where the function of the inactivated genes is restored by the contribution of those derived from the normal parental cells. This family of genes is designated as onco-suppressor genes since their product is necessary for the normal regulated cell growth and is lacking or inactivated in malignant cells. At gene level they should be considered as recessive genetic traits, since the tumor phenotype appears when both alleles of an oncosuppressor gene are inactivated. The mutations affecting their normal functions belong to the type « loss of function ». The molecular analysis of retinoblastoma has led to the cloning and sequencing of the related onco-suppressor gene (RB gene) whose product displays the features of a gene-regulatory protein. In addition, a binding between the RB product and various viral onco-proteins (E1A, large T, E7) has been demonstrated, thus suggesting a mechanism of RB inactivation by which some DNA viruses can transform the host cell. Finally, the increasing availability of DNA markers, defining restriction fragment length polymorphisms, has led to the mapping of the loci of inherited predisposition for familial cancer syndromes such as MEN-1, VHL and NF-2 and to the extension to common cancers of the allele losses analysis that can reveal onco-suppressor gene inactivation. This indirect approach has suggested the occurrence of different onco-suppressor genes for sporadic breast, colonic and lung cancers, bladder carcinoma, germinal tumors of the testis and malignant melanoma. In particular, colonic cancer provides a significant example of a possible multistep scenario for carcinogenesis in humans in which activated oncogenes (e.g. ras) and inactivated putative onco-suppressor genes (on chromosome 17 and 18) coexist in the same cell.