Mechanisms for changing gene expression and their possible relationship to carcinogenesis.

Several genetic or epigenetic events can alter gene expression and we assess their importance in multistage carcinogenesis. Mutation and chromosome rearrangement can produce changes in DNA sequence which have been identified in some cancer cells. Recombination and non-disjunction can lead to the expression of recessive alleles. Overexpression of genes by amplification has also been observed in certain tumours. Heteroploidy, resulting from karyotypic instability, is a common feature of tumorigenicity. Although the pattern of DNA methylation is heritable, there is considerable evidence that genes can be activated by loss of methylation or inactivated by de novo methylation. Hypomethylation is frequently observed in tumour cells. Mutation and chromosome translocation can produce rare specific changes which may be important as initiating events. In contrast, the extent of karyotypic instability and hypomethylation shows some correlation with the stage of tumour progression, and these changes may be important in generating the phenotypic diversity which allows the selection of variants during neoplasia and metastasis. The striking differences between the frequencies of cellular transformation in rodents and man may be more easily explained by differences in the epigenetic controls of gene activity, than by abnormalities in DNA sequence.