What hypothesis explains the necessity of two mutations for pediatric retinoblastoma development?

The two-hit hypothesis, proposed by Alfred Knudson, is fundamental in understanding the genetic basis of retinoblastoma, particularly in pediatric cases. This hypothesis posits that the development of retinoblastoma typically requires two independent mutations affecting both alleles of the Rb1 gene, which is a tumor suppressor gene.

In the context of retinoblastoma, the first "hit" is often a hereditary mutation that is present from birth, which places the individual at risk. The second hit usually occurs later, either sporadically or through environmental factors, leading to the inactivation of the second copy of the Rb1 gene. This dual requirement for mutations explains why retinoblastoma can occur in children who inherit a mutant allele and also elucidates the absence of the disease in individuals with only a single mutation.

This hypothesis not only aligns with the observations of familial and sporadic forms of the disease but also underscores the stochastic nature of cancer development, where multiple genetic changes are necessary for the tumor to progress. Understanding this concept is essential for studying other cancers as well, highlighting the necessity of mutations in both copies of tumor suppressor genes for tumorigenesis.