Drift, draft, waves, and ratcheting: evolutionary models of cancer progression

Recent evidence has found that many mutations are detrimental to tumor growth in cancer. These mutations, called \textit{passenger mutations,} are distinguished from the better known cancer-causing \textit{driver mutations}, which increase a tumor cell's proliferative capacity. How passenger mutations arise, despite selection against them, is not well understood nor fully explained by existing theory. Here, we extend several population genetics models to explain their accumulation in a precancerous population of cells and compare our findings against stochastic simulations. We find that passenger mutations alter and can avert progression to cancer. The probability of cancer depended heavily, and non-monotonically, on both the deleteriousness and rate of mutations. Counter-intuitively, high mutation rates decrease the likelihood of cancer---a finding recently corroborated by clinical data[1]. Our models suggest that therapies exploiting passenger mutations can avert cancer and may be more effective than targeting driver mutations. \begin{enumerate} \item Birkbak, N.J., et al., \textit{Paradoxical relationship between chromosomal instability and survival outcome in cancer.} Cancer Res, 2011. \textbf{71}(10): p. 3447-52. \end{enumerate}