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Mathematical Model Ties Mutations to Time of Colon Cancer Onset

Cancer is a genetic disease, one triggered by a series of gene mutations that ultimately allow a cell to grow without bounds, break loose from its normal home in the body, and metastasize throughout the body. Though it was once thought that as few as three mutations could lead to colon cancer, recent work suggests that as many as 20 mutations may be required for the development of colon cancer. Now, an evolution-based mathematical model provides a mechanism for how colon cancer can develop as a result of a slow accumulation of many mutations, each of which confers a small selective advantage to the pre-malignant cell. This model, which was described in a paper published in the journal PLoS Computational Biology, provides a means of estimating how long it will take nonmalignant colon polyp to become a full-blown tumor.

Working with mutation data from 35 tumor samples, a multi-institutional research team led by Niko Beerenwinkel, Ph.D., of the Swiss Federal Institute of Technology in Basel created a mathematical model based on Wright-Fisher evolutionary theory, which relates the selective advantage that a mutation confers to the number of cells in a population. The model predicts that a few mutations affecting major regulatory pathways confer a large increase in fitness that allows the affected cells to grow into a larger mass of cells. However, multiple subsequent mutations, each with a small but distinct survival advantage, must arise for that mass to become malignant.

The model also suggests that each individual tumor will assemble a unique collection of mutations that depend on how each mutation confers a selective advantage to the developing tumor, which in turn is affected by factors unique to each individual. The researchers note that if their model is correct, the heterogeneity of mutations seen across patients with colon cancer is “a direct consequence of the tumorigenic process itself. “ They add that they believe that this model will be applicable to other slow-growing tumors, such as those in breast, pancreatic, and lung cancer, but not to fast-developing cancers such as leukemias and lymphomas.

This work, which was supported in part by the National Cancer Institute, is detailed in a paper titled, “Genetic Progression and the Waiting Time to Cancer.” This paper is available for downloading at no charge from the journal’s Web site.
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