The two-hit hypothesis

Bui Dac Chi,MDMedic Center

• Much of what scientists know about the origins of cancer and the role of tumor suppressors can be traced back 28 years to the elegant theory of cancer researcher Alfred G. Knudson. Widely thought to be one of the most significant theories in modern biology, Knudson's "two-hit .

• This hypothesis is regconized as an important contribution to our understanding of oncogenesis.

• Thanks to the advent of genetic and molecular technologies which made it possible to trace the origins of certain cancers with high degree of accuracy and contribute to the development of cancer treatments. But have you ever wondered what used to happen several decades back where there was no technology? The scientists could only hypothesise the basis of cancer development and that is how the ‘two-hit hypothesis of cancer’ came into existence by the study of retinoblastoma caused by mutations in the tumour suppressor protein, retinoblastoma protein (pRB).

• “Cancer is, in essence, a genetic disease. Although cancer is complex, and environmental and other nongenetic factors clearly play a role in many stages of the neoplastic process, the tremendous progress made in understanding tumorigenesis in large part is owing to the discovery of the genes, that when mutated, lead to cancer.”

• Cancer is caused by the accumulation of genetic and epigenetic mutations in genes whose products have a role in: 1) directly regulating cell proliferation could be either promoting or inhibiting 2) controlling apoptosis 3) repairing of damaged DNA. These types of genes are grouped into two general categories: tumour suppressor genes (growth inhibiting) and proto-oncogenes (growth promoting).

• During the 1950s and 1960s, cancer epidemiologists were preoccupied with trying to understand the environmental causes of the disease. In a 1953 paper, cancer biologist C. O. Nordling noted that in developed nations, the incidence of cancer seemed to increase with age (C. O. Nordling. Nordling's proposal that the occurrence of cancer needed the accumulation of at least six sequential mutations was ultimately proved wrong. But his idea that cancer is caused by a certain number of 'hits' to the genome paved the way for Knudson's key insight.

• Knudson developed the two-hit hypothesis by statistical methods, without any experimental approaches. He simply compared the time at which both eyes would be affected by retinoblastoma if one or two hits were required and predicted the relative chance of this occurring Knudson’s hypothesis clearly postulated the recessive nature of tumor-initiating gene mutations and the mode of inheritance in familial cancer. This led to the concept of the existence of tumor suppressor genes and loss-of-heterozygosit (LOH) as relevant to carcinogenesis. Notably, Knudsonalready mentioned the possibility of “delayed mutation” that may correspond to germline-mosaic mutations. Including this possibility, his insights facilitated the development ofthe field of cancer genetics. The first molecular cloning of the tumor suppressor gene RB1, the predisposing gene for retinoblastoma, was achieved in 1986.

• “The data presented here and in the literature are consistent with the hypothesis that at least one cancer, retinoblastoma, can be caused by two mutations…. One of these mutations may be inherited as a result of a previous germinal mutation…. Those patients that inherit one mutation develop tumors earlier than do those who develop the nonhereditary form of the disease; in a majority of cases those who inherit a mutation develop more than one tumor

Individuals will develop cancer of the retina if they either inherit one mutated retinoblastoma (Rb) gene and incur a second mutation (possibly environmentally induced) after conception, or if they incur two mutations or hits after conception.3 If only one Rb gene functions normally, the cancer is suppressed. Knudson dubbed these preventive genes anti-oncogenes; other scientists renamed them tumor suppressors

• 1998 Lasker~DeBakey Clinical Medical Research Award - Alfred Knudson, Jr.