Only three driver gene mutations are required for the development of lung and colorectal cancers

Abstract

Cancer arises through the sequential accumulation of mutations in oncogenes and tumor suppressor genes. However, how many such mutations are required for a normal human cell to progress to an advanced cancer? The best estimates for this number have been provided by mathematical models based on the relation between age and incidence. For example, the classic studies of Nordling [Nordling CO (1953) Br J Cancer 7(1):68-72] and Armitage and Doll [Armitage P, Doll R (1954) Br J Cancer 8(1):1-12] suggest that six or seven sequential mutations are required. Here, we describe a different approach to derive this estimate that combines conventional epidemiologic studies with genome-wide sequencing data: incidence data for different groups of patients with the same cancer type were compared with respect to their somatic mutation rates. In two well-documented cancer types (lung and colon adenocarcinomas), we find that only three sequential mutations are required to develop cancer. This conclusion deepens our understanding of the process of carcinogenesis and has important implications for the design of future cancer genome-sequencing efforts.

Keywords: cancer; cancer evolution; cancer incidence; driver mutations; somatic mutation rate.

Fig. 1.

Distributions of the total number of somatic mutations and of the somatic mutation rates (somatic mutations per year) in smokers (blue) and never-smokers (red) in LUAD. The rightmost parts of the red distributions have been excluded to facilitate comparison. Distributions of the number of somatic mutations (A) and of the somatic mutation rates (B).

Fig. 2.

Distributions of the total number of somatic mutations (A and C) and of the somatic mutation rates (somatic mutations per year) (B and D) in MMR-proficient (MSS or MLH1-normal) and MMR-deficient (MSI or MLH1-silent) CRCs. The rightmost parts of each red distribution have been excluded to facilitate comparison.

Fig. 3.

Relation between the number of rate-limiting driver mutations and the increase in LUAD incidence observed in smokers. The observed average increase in LUAD incidence associated with smoking is 16.2-fold (red line); the pink area is its 99% CI (10.25–25.6) (23). The expected increase in LUAD incidence associated with the indicated number of rate-limiting mutations is represented by the blue marks, with the corresponding 95% CI indicated by blue vertical segments.

Fig. 4.

Relation between the number of rate-limiting driver mutations and the increase in CRC incidence observed in patients with MMR deficiency. The observed average increase in incidence associated with MMR deficiency is 114.2-fold (red line); the pink area is its 95% CI (60.7–217) (14). The expected increase in CRC incidence associated with the indicated number of rate-limiting mutations is represented by the blue marks, with the corresponding 95% CI indicated by blue vertical segments.