Book of Abstracts: Albany 2011
June 14-18 2011
©Adenine Press (2010)
Evolutionary Model of Cancer Progression: Understanding the Role Of Passenger Mutations In Cancer Progression
The development of cancer can be considered an evolutionary process within an organism: cells acquire mutations, compete for resources, and are subject to natural selection. During this transformation, malignant tissues acquire tens of thousands of somatic mutations, yet only a handful are believed to be responsible for the cancer phenotype, termed driver mutations (1). The rest, occurring sporadically across cancer genomes, are called passenger mutations. We hypothesize that many passenger mutations may be deleterious to cancer cells, yet occasionally fixate in the population.
We developed a stochastic, evolutionary model of cancer progression where cells may acquire both driver mutations (advantageous to the cells) and passenger mutations (deleterious to the cells). We found that many passengers fixate in neoplastic populations, despite purifying selection against them, via a mechanism similar to Muller’s Ratchet (2) and by hitchhiking with driver mutations. An analysis of known somatic mutations in cancer found that many passenger mutations are predicted to be deleterious to human cells, based on their reduction in protein stability and occurrence at conserved loci—corroborating our model's findings. We also found that biophysical properties of driver mutations may distinguish oncogenes from tumor suppressors.
Through combined analytical and computational analysis, we identified two phases of neoplastic behavior: one where driver mutations dominate dynamics and the population grows exponentially, and another where passenger mutations overwhelm the cells causing prolonged dormancy or regression. We found that the conditions for dormancy and regression may be most exploitable in early metastases and are currently testing our findings in a mouse model.
Christopher D. McFarland1
1 Harvard University Graduate Biophysics Program