Abstract
Cancer results from genetic alterations that disturb the normal cooperative behavior of cells. Recent high-throughput genomic studies of cancer cells have shown that the mutational landscape of cancer is complex and that individual cancers may evolve through mutations in as many as 20 different cancer-associated genes. We use data published by Sjöblom et al. (2006) to develop a new mathematical model for the somatic evolution of colorectal cancers. We employ the Wright-Fisher process for exploring the basic parameters of this evolutionary process and derive an analytical approximation for the expected waiting time to the cancer phenotype. Our results highlight the relative importance of selection over both the size of the cell population at risk and the mutation rate. The model predicts that the observed genetic diversity of cancer genomes can arise under a normal mutation rate if the average selective advantage per mutation is on the order of 1%. Increased mutation rates due to genetic instability would allow even smaller selective advantages during tumorigenesis. The complexity of cancer progression can be understood as the result of multiple sequential mutations, each of which has a relatively small but positive effect on net cell growth.
Highlights
The current view of cancer is that tumorigenesis is due to the accumulation of mutations in oncogenes, tumor suppressor genes, and genetic instability genes [1]
Sjoblom et al [7] have recently determined the sequence of 13,000 genes in colorectal cancers and found that individual tumors contained an average of 62 nonsynonymous mutations
Recent sequencing projects of cancer cells suggest that mutations in up to 20 different genes might be responsible for driving an individual tumor’s development
Summary
The current view of cancer is that tumorigenesis is due to the accumulation of mutations in oncogenes, tumor suppressor genes, and genetic instability genes [1]. Sequential mutations in these genes lead to most of the hallmarks of cancer [2]. Theoretical considerations have suggested that a handful of mutations, perhaps as few as three, may be sufficient for developing colorectal cancer [4,5] This relatively small number is consistent with the standard model for colorectal tumorigenesis based on the identification of mutations in well-known cancer genes [6]. Extrapolating to the entire genome, it was estimated that individual colorectal cancers contain about 100 nonsynonymous mutations and that as many as 20 of the mutated genes in individual cancers might play a causal role in the neoplastic process [7]
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