Why are two "hits" required to inactivate tumor-suppressor genes?

Inactivation of tumor-suppressor genes often requires two "hits" due to the nature of how these genes function and the genetic makeup of individuals. Tumor-suppressor genes typically exist in pairs, as individuals inherit one allele from each parent. For a tumor-suppressor gene to be fully inactivated, both alleles must undergo mutation or deletion—this is commonly referred to as the "two-hit hypothesis."

When one allele is mutated (the first "hit"), the remaining healthy allele can compensate for the loss of function. Thus, the presence of one normal allele allows for the regulation of cell growth and division, preventing the unchecked proliferation characteristic of cancer cells. Only when the second allele is subsequently mutated or lost does the cell fully lose the tumor-suppressing capability, leading to potential unregulated cell growth and the development of tumors. This dual requirement underscores the importance of both alleles in maintaining normal cellular functions and illustrates the genetic basis of certain inherited cancer predispositions, such as those seen in familial forms of cancers like retinoblastoma and Li-Fraumeni syndrome.

This understanding provides a clear framework for comprehending the mechanisms behind tumorigenesis and the significance of genetic mutations in cancer biology.