ABSTRACT
Tumor suppressor genes are responsible for the inhibition of unchecked cellular proliferation. These genes were first speculated to exist when combinations of tumor cells and normal cells produced hybrids that lacked the proliferative capacities of malignant cells, but showed characteristics of the normal cell line.1 While studying pediatric retinoblastoma in 1971, Knudson proposed that two allelic events or ‘hits’ were necessary for conversion to a malignant cell. In heritable cancers, the first event was proposed to be a germline mutation leading to allelic heterogeneity.2 The second event would then be a somatic mutation leading to a loss of heterozygosity (LOH) and the malignant phenotype.This became known as the ‘two-hit hypothesis’ (Figure 4.1). In sporadic cancers, one ‘hit’ is usually a point mutation, while the second ‘hit’ is usually deletion of all or a part of a chromosome. In fact, the second ‘hit’ in both sporadic and heritable cancers may come from any number of mechanisms, including nondisjunction, mitotic recombination, deletion, point mutation, or silencing due to methylation. Although the two-hit hypothesis is a widely recognized model for the development of hereditary cancers, it should not be extrapolated to tumors beyond heritable
pediatric cancers, for which it was originally described.3
