Knudson hypothesis

The Knudson hypothesis is the famous reasoning that first explained why some cancers run in families and strike early while the same cancer in others appears later and just once. The clever part is that Alfred Knudson worked it out not by looking at genes directly, but by studying how the timing and pattern of a childhood eye cancer differed between families.

Studying retinoblastoma in the 1970s, Knudson noticed that inherited cases often appeared early and in both eyes, while non-inherited cases appeared later and in one eye. He proposed that two separate mutational events, two hits, are needed to start the tumor. Children who inherit one hit already have it in every retinal cell and need only one more, so cancer comes sooner and in more places.

This insight predicted the existence of tumor-suppressor genes years before one was found, and the gene RB1 later confirmed it beautifully. The hypothesis underpins the broader two-hit model for many tumor suppressors. It remains foundational, even though we now know real cancers often need more than two events and many cooperating genes.