A large number of familial and sporadic cancers are mechanistically explainable in terms of Knudson's original model, or a modification of this model. The processes by which genetically identical alleles may be rendered functionally different are genome imprinting and nucleotide sequence changes. There are two important differences between alleles inactivated by imprinting and alleles inactivated by nucleotide sequence changes. The first is that the inactivation of an allele by imprinting is reversible and epigenetic. Thus, the imprinted alleles do not carry a “mutation.” The second difference concerns the specificity of allele inactivation. In the absence of any epigenetic inactivation events, models that seek to correlate progressional changes with genetic events invoke a relatively large number of independent mutations, all of which must occur somatically, within the same cell. In the case of advanced stage glioblastoma, for example, loss of heterozygosity is observed at loci on three different chromosomes. The probability that three mutations have occurred independently, each followed by a nondisjunction or mitotic recombination event, is considered to be very low.
ASJC Scopus subject areas
- Cancer Research