Genetic and molecular aspects of human multigenerational carcinogenesis.
The notion that cancer is a genetic disease has gained increasing credence from the now numerous studies in which specific alterations of chromosome and of gene structure and activity in a variety of cancers have been identified, and, in particular, with the increasing awareness of the heritability of factors that predispose to the development of early, specific cancers in the offspring of parents carrying these predisposing genes. That the inheritance of a single allele is a major causal factor in certain childhood cancers, e.g., retinoblastoma and Wilms' tumour, has long been known, and the locations of the genes predisposing to these tumours have been mapped and at least one has been isolated. Over the past year, using genetic analysis, a further five different loci have been mapped that are involved in five other inherited cancer predispositions. Moreover, in most of these cases the evidence again suggests that one of the pair of alleles at the locus linked to the predisposition undergoes somatic mutation (loss) within the cells that give rise to each of these tumours. A major factor in the origin of these tumours therefore is a loss of a tumour suppressing role of the loci in question. At the present time, seven such suppressor loci on six different chromosomes have been identified, and in a number of cases evidence has been presented for the occurrence of other specific genetic changes that may be necessary for the emergence of a neoplasm. Specific gene or chromosome loss is, however, not confined to cancers associated with the inheritance of a single gene but is increasingly being observed in various more common sporadic cancers, and these data are reviewed and some new data presented. Studies on sporadic cancers have revealed a wide range of different oncogenes in which mutation or abnormal regulation is a cardinal factor leading to a neoplastic state. The products of many of these oncogenes have homologies to growth factors, growth factor receptors or are signal or DNA binding proteins, and specific mutations have been characterized in a number of e-oncogenes in neoplastic human cells. In contrast to genes which may suppress neoplasia, the c-oncogenes act as positive factors, although the presence of a single mutated oncogene is not sufficient on its own to result in neoplastic transformation.(ABSTRACT TRUNCATED AT 400 WORDS)
Evans
H J
HJ
Medical Research Council, Human Genetics Unit, Western General Hospital, Edinburgh, UK.
D000818:Animals; D005134:Eye Neoplasms / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics; D008745:Methylation; D009154:Mutation; D009369:Neoplasms / Q000235:genetics*; D012175:Retinoblastoma / Q000235:genetics; D009396:Wilms Tumor / Q000235:genetics