Quantifying Clonal and Subclonal Passenger Mutations in Cancer Evolution.

Ivana Bozic,Jeffrey M Gerold,Martin A Nowak,Edwin Wang

doi:10.1371/journal.pcbi.1004731

Ivana Bozic, Jeffrey M Gerold + Show 2 more

Open Access

https://doi.org/10.1371/journal.pcbi.1004731

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Abstract

The vast majority of mutations in the exome of cancer cells are passengers, which do not affect the reproductive rate of the cell. Passengers can provide important information about the evolutionary history of an individual cancer, and serve as a molecular clock. Passengers can also become targets for immunotherapy or confer resistance to treatment. We study the stochastic expansion of a population of cancer cells describing the growth of primary tumors or metastatic lesions. We first analyze the process by looking forward in time and calculate the fixation probabilities and frequencies of successive passenger mutations ordered by their time of appearance. We compute the likelihood of specific evolutionary trees, thereby informing the phylogenetic reconstruction of cancer evolution in individual patients. Next, we derive results looking backward in time: for a given subclonal mutation we estimate the number of cancer cells that were present at the time when that mutation arose. We derive exact formulas for the expected numbers of subclonal mutations of any frequency. Fitting this formula to cancer sequencing data leads to an estimate for the ratio of birth and death rates of cancer cells during the early stages of clonal expansion.

Highlights

In healthy tissues, cell division and cell death are tightly controlled processes, which enable a precise balance assuring that the number of cells in the body remains approximately constant
We show that the frequencies obtained by passenger mutations depend strongly on the ratio of death and birth rates of cancer cells
We estimate the size of the cancer cell population that was present when a specific mutation first emerged

Summary

Introduction

Cell division and cell death are tightly controlled processes, which enable a precise balance assuring that the number of cells in the body remains approximately constant. During each cell division mistakes in DNA replication can occur, leading to accumulation of mutations in individual cells [1, 2] The majority of such mutations are effectively neutral (passengers), but some of them (drivers) can provide selective advantage to the cell, by tipping the balance of cell division and death slightly in favor of increased proliferation [3,4,5]. This unwanted evolution [6,7,8] of somatic cells can lead to a clonal expansion of cells with driver mutations, which can result in the formation of tumors and seeding of new lesions in distant tissues [9,10,11]. Passenger mutations can provide information about the timing of cancer evolution in individual patients by acting as a molecular clock [15]

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