Estimating the number of genetic mutations (hits) required for carcinogenesis based on the distribution of somatic mutations

Individual instances of cancer are primarily a result of a combination of a small number of genetic mutations (hits). Knowing the number of such mutations is a prerequisite for identifying specific combinations of carcinogenic mutations and understanding the etiology of cancer. We present a mathematical model for estimating the number of hits based on the distribution of somatic mutations. The model is fundamentally different from previous approaches, which are based on cancer incidence by age. Our somatic mutation based model is likely to be more robust than age-based models since it does not require knowing or accounting for the highly variable mutation rate, which can vary by over three orders of magnitude. In fact, we find that the number of somatic mutations at diagnosis is weakly correlated with age at cancer diagnosis, most likely due to the extreme variability in mutation rates between individuals. Comparing the distribution of somatic mutations predicted by our model to the actual distribution from 6904 tumor samples we estimate the number of hits required for carcinogenesis for 17 cancer types. We find that different cancer types exhibit distinct somatic mutational profiles corresponding to different numbers of hits. Why might different cancer types require different numbers of hits for carcinogenesis? The answer may provide insight into the unique etiology of different cancer types.Author summary: Cancer is primarily a result of genetic mutations. Each individual instance of cancer is initiated by a specific combination of a small number of mutations (hits). In trying to identify these combinations of mutations, it is important to know how many hits to look for. However, there are conflicting estimates for the number of hits. We present a fundamentally different model for estimating the number of hits. We found that the number hits ranges from two-eight depending on cancer type. These findings may provide insight into the unique characteristics of different cancer types.