Cancer develops through a process of accumulated genetic changes over time. The multi-hit hypothesis posits that a normal cell becomes cancerous through a series of alterations, or “hits,” to its DNA. Each hit affects genes that regulate cell growth and division, pushing the cell toward uncontrolled proliferation. This model explains that cancer is the culmination of multiple molecular missteps and clarifies the interplay between genetic predispositions and environmental factors.
The Original Two-Hit Model
The foundation of the multi-hit hypothesis was laid in 1971 by physician and geneticist Alfred Knudson. Through his statistical analysis of retinoblastoma, a rare childhood cancer of the retina, Knudson proposed the “two-hit” model. He observed that the cancer manifested in two distinct patterns: a hereditary form appearing at a young age, often in both eyes, and a sporadic, non-hereditary form appearing later and affecting only one eye.
To explain this disparity, Knudson theorized that two separate mutational events were necessary to trigger the cancer. In hereditary cases, the first mutation is inherited and present in every cell from birth. This means only one additional, spontaneous mutation—the second hit—is needed in a retinal cell for a tumor to form. Because there are millions of retinal cells, the probability of this second hit occurring is high, explaining the early onset and bilateral tumors.
In the sporadic form, two separate mutations must occur by chance in the same single retinal cell. The likelihood of two independent errors striking the same cell is exceedingly low, which accounts for the later onset and unilateral tumors. Knudson’s model was the first to provide a clear, mechanistic link between hereditary and spontaneous forms of a cancer, proposing that both were caused by inactivating the same gene.
The Nature of Genetic Hits
Genetic “hits” are alterations that damage or inactivate a gene involved in controlling cell behavior. These mutations primarily affect two major classes of genes: tumor suppressor genes and proto-oncogenes. Tumor suppressor genes are the cellular “brakes,” producing proteins that slow cell division, repair DNA mistakes, or tell cells when to die in a process called apoptosis. For these genes, both copies must be inactivated for their protective function to be lost, which aligns with Knudson’s two-hit model.
Proto-oncogenes are the cell’s “accelerators,” encoding proteins that stimulate normal cell growth and division. When a proto-oncogene is mutated, it can become an “oncogene,” a permanently activated version that promotes continuous cell proliferation. Unlike tumor suppressor genes, a single “hit” in just one copy of a proto-oncogene can be enough to drive a cell toward cancer.
These genetic hits are not always simple mutations in the DNA sequence. They can also include epigenetic changes, which are modifications that alter gene activity without changing the DNA code itself. Other hits might involve larger-scale chromosomal abnormalities, such as the loss of a piece of a chromosome that contains a tumor suppressor gene.
Progression from Two Hits to Multiple Hits
While the two-hit model explained retinoblastoma, it became clear that most adult cancers are more complex. Cancers of the colon, lung, and breast result from an accumulation of numerous genetic hits over many years. This led to the evolution of the two-hit model into the more comprehensive multi-hit hypothesis, better reflecting the genetics of common malignancies.
This progression helps explain the strong correlation between cancer and aging. As individuals get older, their cells have had more time to divide, and with each division comes a small chance of a new mutation. Over a lifetime, the odds increase that a single cell line will accumulate the necessary sequence of multiple hits to genes that govern cell behavior. This is why cancer incidence rises with age; there has been more opportunity for molecular errors to build up.
The process is often accelerated by clonal expansion. When a cell sustains an initial hit that gives it a slight growth advantage, it divides more than its neighbors, creating a clone of identical cells. If a cell within this clone acquires a second hit, it gains a further advantage and outcompetes the surrounding cells. This step-by-step process of mutation and selection continues, with each successive hit driving the cells closer to a fully malignant state.
Implications for Cancer Risk and Development
The multi-hit hypothesis explains why certain factors increase a person’s cancer risk. For individuals with an inherited mutation in a tumor suppressor gene like BRCA1 or BRCA2, the “first hit” is already present in every cell. This inherited predisposition means fewer additional hits are required for cancer to develop, increasing their lifetime risk for breast, ovarian, and other cancers.
The model also explains the role of carcinogens. Exposure to substances like the chemicals in tobacco smoke or ultraviolet (UV) radiation from the sun increases the rate at which new mutations, or “hits,” occur in cells. These environmental exposures accelerate the timeline for cancer development by causing widespread DNA damage, making it more likely that a cell will acquire the necessary combination of hits.
This understanding also highlights why lifestyle factors influence cancer risk. For example, sustained obesity can create a pro-inflammatory environment that encourages cells to divide more rapidly. This increased rate of cell division means more opportunities for random mutations to occur during DNA replication, raising the probability of accumulating the multiple hits needed for tumor formation.