Tumor Suppressor Genes - Two-hit Hypothesis

Two-hit Hypothesis

Unlike oncogenes, tumor suppressor genes generally follow the "two-hit hypothesis," which implies that both alleles that code for a particular protein must be affected before an effect is manifested. This is because if only one allele for the gene is damaged, the second can still produce the correct protein. In other words, mutant tumor suppressors' alleles are usually recessive whereas mutant oncogene alleles are typically dominant. The two-hit hypothesis was first proposed by A.G. Knudson for cases of retinoblastoma. Knudson observed that the age of onset of retinoblastoma followed 2nd order kinetics, implying that two independent genetic events were necessary. He recognized that this was consistent with a recessive mutation involving a single gene, but requiring biallelic mutation. Oncogene mutations, in contrast, generally involve a single allele because they are gain-of-function mutations. There are exceptions to the "two-hit" rule for tumor suppressors, such as certain mutations in the p53 gene product. p53 mutations can function as a "dominant negative," meaning that a mutated p53 protein can prevent the function of normal protein from the un-mutated allele. Other tumor-suppressor genes that are exceptions to the "two-hit" rule are those that exhibit haploinsufficiency for example PTCH in medulloblastoma. An example of this is the p27Kip1 cell-cycle inhibitor, in which mutation of a single allele causes increased carcinogen susceptibility.