two-hit hypothesis

The two-hit hypothesis says that some safety features come in pairs, and you need to break both before the danger appears. Picture a door with two independent locks: as long as one lock holds, the door stays shut. Only when both locks are broken does the door swing open. For many tumor-suppressor genes, the two locks are the two copies of the gene.

Because we inherit two copies of most genes, one from each parent, a single damaged copy of a tumor-suppressor gene usually leaves a working backup that still protects the cell. Cancer risk from that gene rises sharply only after the second, remaining copy is also lost or disabled, the so-called second hit. The hits can come from mutation, deletion, silencing, or loss of heterozygosity.

This idea, proposed by Alfred Knudson to explain retinoblastoma, neatly distinguishes inherited from sporadic cancers. A person who inherits one broken copy already carries the first hit in every cell and needs only one more event, which is why hereditary cancers can appear earlier and in more than one place. The model is a powerful guide, though real tumors often involve many genes and more than two events.