The genetics of childhood cancer

INTRODUCTION OVERWHELMING EVIDENCE implicates a complex interaction of abnormal intraand extracellular genetic events in the development of cancer. Neoplasia is a dynamic multistep process that ultimately drives a normal cell to proceed towards malignant transformation. The number of steps, their chronological order and the nature of particular genetic events specific to each tumour type are objectives of ongoing studies. Childhood cancers are unique in that their early age of onset suggests that underlying inherited constitutional genetic defects might provide a strong predisposing influence. For example, childhood cancers are common in single-gene disorders, such as neurofibromatosis type I and Beckwith-Wiedemarm syndrome, as well as in DNA breakage sydromes, including Fanconi’s anaemia and Bloom’s syndrome, in which the ability to repair damaged DNA is impaired as a result of deficiencies or defects of specific inherited repair enzymes. The pedigree of a child with cancer often demonstrates other affected family members, suggesting that vertical transmission of a defective or altered gene from generation to generation plays a causative role in cancer development. Various poorly-defined environmental factors may interact with the underlying genetic background of the host to determine the precise phenotype of such childhood and familial cancers. Nevertheless, in only a small percentage of cases of human cancer does evidence for hereditary or familial influences exist 111. This review outlines the roles of the “dominant” oncogenes and “recessive” tumour suppressor genes known to be involved in the formation of paediatric malignancies. Table 1 indicates well characterised genes associated with paediatric tumours. In addition, the genetics of familial cancer syndromes and genomic imprinting will be discussed as they apply to childhood cancer. The clinical relevance of genetic factors in the aetiology of paediatric cancer is discussed, as well as issues surrounding the role of predictive genetic testing for this population of cancer patients. Initiation, promotion, progression and metastasis represent the stepwise stages of human carcinogenesis. At each of these stages, one or several genetic events occur in what are thought to be critical normal cellular growth regulatory pathways. Knudson’s original “two-bit” hypothesis of carcinogenesis [2] suggests that both alleles of one gene need to be altered for turnour formation to occur in tissues with relatively few genetic checkpoints and controls, and the paradigm for this hypothesis is retinoblastoma. The model has now been expanded to