Cancer development is something that has been researched for many decades and with the advent of genetic and molecular technologies, it is now possible to track down the origins of certain cancers with high degree of accuracy. However, several decades back, the scientists were left to hypothesize the basis of cancer development and the ‘two-hit theory of cancer development’ is one such hypothesis gained popular as the ‘Knudson hypothesis’.
Although the hypothesis gained popularity as ‘Knudson hypothesis’, the basis for his suggestions came from a scientist called Carl O. Nordling as far back as 1953. The proposal made by Nordling described a multi-mutation theory on cancer and it postulated that the increase in the incidence of cancer in industrialized nations, which roughly equals to the sixth power of age, could be explained by having six consecutive mutations accumulating over time and therefore giving rise to an outbreak of cancer. However, it was Knudson who further studied this theory and came up with the notion of ‘two-hit theory’ which postulated that although multiple ‘hits’ to DNA was necessary for cancers to take place, the number of hits could be only ‘two’ as against ‘six’ suggested by Nordling.
Accordingly, the Knudson hypothesis explains that, in the case of inherited cancers, the first insult take place at conception or before birth and those who have received such a genetic insult are more susceptible to develop a cancer as soon as a ‘second hit’ affects their genetic constituency. However, in the non-inherited form of cancers, both hits are received after birth. Thus, according to Knudson, a cancerous cell will have two mutated genes in the same location while a single mutation does not necessarily cause a cancer.
The study undertaken by Knudson in proving his hypothesis was a study in relation to retinoblastoma, which is a tumor occurring both as a inherited and a sporadic disease. In the inherited form, children would develop retinoblastioma at an early age than when the disease manifest as a sporadic event. At the same time, having both eyes affected would mean that there is an underlying genetic predisposition than a localized insult. Thus, Knudson postulated that children who developed retinoblastoma do so because they inherit a mutated gene from their parents and later received a second ‘hit’ to the same gene in the second chromosome, leading to the rapid formation of a cancer. The sporadic cases on the other hand, receive both hits during life, and therefore will take more time to manifest than its inherited counterpart.
The ‘two-hit’ theory of cancer development lead to the isolation of cancer related genes and as science grew, researchers were able to pinpoint the potential ‘hits’ to the cancer suppressor gene and the proto-oncogenes which controls the excessive growth of cells. However, without affecting both genes, the potential for cancer formation is unlikely, which further strengthens the ‘two-hit theory of cancer development’ postulated by Knudson.
