Credit: The Stock Solution

Studies of cancer biology and genomics have mainly focused on recurrent driver mutations in key oncogenes and tumour suppressor genes, as these are known to have major roles in tumorigenesis and cancer progression. However, these driver mutations are vastly outnumbered by passenger mutations, which are often assumed to be biologically neutral. A new computational study suggests that passenger mutations may have detrimental effects on tumour fitness, with therapeutic implications.

Random unselected mutations are expected to be, on average, mildly deleterious (that is, they confer a small selective disadvantage). So, Leonid Mirny and colleagues incorporated deleterious passenger mutations into their computer simulations of tumour evolution. In their model, each cancer cell can stochastically die or divide, and the cell divisions can be accompanied by the frequent acquisition of a deleterious passenger mutation or the rare acquisition of a growth-promoting driver mutation.

these passenger mutations were indeed moderately deleterious

The simulations resulted in population dynamics in which tumours grew in a sawtooth manner: each acquisition of a driver event resulted in the rapid expansion of the tumour cell population, which was followed by a gradual decline in cell number owing to passenger mutation accumulation until the next driver mutation occurred. Importantly, accounting for deleterious passenger mutations recapitulated some known features of tumour biology, such as dormancy and regression, that are not seen in simpler simulations.

Interestingly, despite the deleterious nature of the simulated passenger mutations, large numbers of passenger mutations accumulated and spread throughout the tumour cell population. This partly occurred by mechanisms that are known from population genetics studies. For example, the positive selection of cells containing driver mutations can increase the frequency of passenger mutations co-occurring in these cells (an effect that is known as genetic hitch-hiking). Overall, this indicates that even mutations that are found throughout a large proportion of cells in a particular tumour might actually exert a negative fitness effect.

So, is there evidence that passenger mutations found in clinical tumours can be genuinely deleterious or might real tumours retain only selectively neutral passenger mutations? The authors assessed the deleteriousness of passenger mutations in the Catalogue of Somatic Mutations in Cancer (COSMIC) database. They used the PolyPhen program, which scores deleteriousness according to the extent to which the mutation has been avoided (selected against) during organismal evolutionary history. On average, these passenger mutations were indeed moderately deleterious, and substantially more so than single-nucleotide polymorphisms underlying normal human population variation. However, it is worth noting that deleteriousness of a mutation during normal organismal evolution might not fully reflect the fitness effects on cancer cells, which typically have altered cell death and checkpoint mechanisms.

Finally, the authors ran simulations and found that enhancing the detrimental effects of passenger mutations — such as by reducing the ability of cancer cells to buffer deleterious mutations — resulted in sustained tumour regression. In practice, such buffering mechanisms include the proteasome and chaperone systems. As pharmacological inhibitors of these systems have been developed that show antitumour activity in some settings, it will be interesting to determine the extent to which sensitivity to these agents is conferred by many accumulated passenger events versus a few key oncogenic mutations.