The effect of one additional driver mutation on tumor progression

Evolutionary Applications

Johannes G. Reiter¹  Ivana Bozic²  Benjamin Allen¹  Krishnendu Chatterjee¹ 

[1] IST Austria (Institute of Science and Technology Austria), Klosterneuburg, Austria;Program for Evolutionary Dynamics, Harvard University, Cambridge, MA, USA

关键词: branching process;    cancer;    clonal expansion;    density dependence;    driver mutation;    stochastic models;   

DOI  :  10.1111/eva.12020

来源: Wiley

【 摘 要 】

Abstract

Tumor growth is caused by the acquisition of driver mutations, which enhance the net reproductive rate of cells. Driver mutations may increase cell division, reduce cell death, or allow cells to overcome density-limiting effects. We study the dynamics of tumor growth as one additional driver mutation is acquired. Our models are based on two-type branching processes that terminate in either tumor disappearance or tumor detection. In our first model, both cell types grow exponentially, with a faster rate for cells carrying the additional driver. We find that the additional driver mutation does not affect the survival probability of the lesion, but can substantially reduce the time to reach the detectable size if the lesion is slow growing. In our second model, cells lacking the additional driver cannot exceed a fixed carrying capacity, due to density limitations. In this case, the time to detection depends strongly on this carrying capacity. Our model provides a quantitative framework for studying tumor dynamics during different stages of progression. We observe that early, small lesions need additional drivers, while late stage metastases are only marginally affected by them. These results help to explain why additional driver mutations are typically not detected in fast-growing metastases.

【 授权许可】

CC BY   
© 2012 The Authors. Evolutionary Applications published by Blackwell Publishing Ltd.

Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.