In 1971 Alfred Knudson's described his “two-hit” mutation model for retinoblastoma, giving the underlining theory for genetic research. The first“hit” is a germline mutation and therefore is found in all somatic cells of the offspring. The second “hit” is a single cell mutation during the mitotic cell cycle. The chance of one mutation is greater than the chance of two. If the mutation occurs in a retinal cell, a retinoblastoma will develop(9).
Knudson's two-hit hypothesis. Note that the hereditary pedigree appears similar to one of a dominant trait. Suppose there are 1 million target cells and the probability of mutation is 10^-5 per cell. Sporadic retinoblastoma requires two hits and will affect 1 person in 10, 000 (10^6 × 10^-5 × 10^-5 = 10^-4 ), while the familial form requires only one hit and will be quite highly penetrant (10^6 × 10^-5 = > 1).