What does the "two-hit hypothesis" pertain to?

The "two-hit hypothesis" pertains to the requirement for both alleles of a tumor suppressor gene to be inactivated in order for cancer to develop. This concept was first introduced by researcher Alfred Knudson in the context of retinoblastoma, a type of eye cancer. According to the hypothesis, the first “hit” refers to a mutation or deletion of one allele, which does not lead to cancer on its own. Only when the second "hit" occurs, affecting the second allele, does it lead to the loss of the gene's function and allow uncontrolled cellular proliferation, resulting in cancer. This framework highlights the critical role of tumor suppressor genes in regulating cell growth and maintaining cellular integrity, emphasizing that both alleles need to be compromised for a malignant transformation to take place.