Alfred G. Knudson Jr.

Alfred Knudson proposed the two-hit hypothesis in 1971, one of the most influential conceptual contributions to cancer biology. Analyzing the occurrence of retinoblastoma, he deduced from epidemiological patterns that two mutational events were required for tumor formation, with hereditary cases carrying one germline mutation (first hit) requiring only one additional somatic event (second hit). This hypothesis correctly predicted the existence of tumor suppressor genes and explained the mechanism of hereditary cancer predisposition syndromes. The subsequent cloning of RB1 as the first tumor suppressor gene confirmed his hypothesis, and the concept now underpins understanding of BRCA1/2, APC, TP53, CDKN2A, and all other tumor suppressor genes.