Knudson's Two-Hit Hypothesis

In 1971, Alfred Knudson studied retinoblastoma, a childhood eye tumor. Children with a family history developed tumors early and often in both eyes; sporadic cases were later and usually in one eye. He proposed that the tumor needs two hits — both copies of a gene must be lost.

In hereditary cases, every cell already carries one bad copy from birth, so only one more hit is needed. In sporadic cases, the same cell must be unlucky twice. The gene turned out to be RB1.

The second hit often happens by loss of heterozygosity (LOH): the remaining good allele is deleted, or the chromosome region is replaced by a copy of the mutant one via mitotic recombination. Some suppressors are silenced instead by promoter hypermethylation — an epigenetic hit.

Exceptions exist. Some genes are haploinsufficient (one copy isn't enough), and mutant p53 can act dominant-negative, poisoning the normal protein it pairs with.

Gatekeepers directly control growth or death (RB1, APC, p53). Caretakers maintain the genome (BRCA1/2, mismatch-repair genes); losing them doesn't cause growth directly but speeds up mutation everywhere.