Accumulation of Oncogenic Mutations During Progression from Healthy Tissue to Cancer

by Ruibo Zhang and Ivana Bozic

Carcinogenesis is a multi-stage process in which driver gene mutations occur sequentially. Understanding the arrival times of genetically different subclones provides important insights into tumorigenesis. In this work, we establish a multi-type branching process to model the initiation of cancer that starts from a healthy tissue in homeostasis. Mutations can be either neutral or advantageous, which reflects that inactivating a single copy of a tumor suppressor gene does not directly provide a selective growth advantage. We approximate the distribution of the arrival time for each type and compare it to computer simulations of the process. The results are applied to study the initiation of colorectal cancer and chronic myeloid leukemia. 

Model illustration. The model describes an evolutionary process that starts with a large healthy population in homeostasis (blue circles). Mutations that are either neutral or advantageous occur sequentially, which causes subsequent types to be either homeostatic (yellow) or initiated (orange). The cancerous type (red) emerges only when all the required genetic alterations have taken place.