Haplo-insufficiency? Let me count the ways

During the course of cancer development, a normal cell progresses toward malignancy by acquiring a specific series of mutations. These include mutations that activate otherwise innocuous proto-oncogenes, and others that inactivate recessive tumor suppressor genes. By acquiring these mutations, a cell progressively alters its phenotype, and thereby eludes the various controls that normally prevent malignant growth in an organism. Based on epidemiological data (Renan 1993), and consistent with in vitro experimental data (Hahn et al. 1999), it is estimated that between four and eight rate-limiting mutations occur during the development of most human cancers. But this raises a conundrum. The incidence of cancer should be proportional to the number of rate-limiting events necessary for tumorigenesis, the frequency of these events, and the size of the target cell population for these events. Therefore, given that somatic mutations arise at a frequency of <6 × 10⁻⁶ per locus (Seshadri et al. 1987), an overly simplistic calculation would suggest that even a tumor requiring only four mutations would only arise at a frequency of ∼1 in 10⁻²¹ cells, a vanishingly low frequency even in an organism composed of ∼10¹⁴ cells, as humans are. Why, then, are the odds of developing cancer during one's lifetime ∼1 in 3, and what does this tell us about the mechanisms that operate during tumorigenesis?

At least two factors confound the simplicity of the above calculation. The first concerns the frequency of occurrence of the rate-limiting events. In tumors, genes may be epigenetically silenced by methylation as well as inactivated by genetic mutation (Jones and Laird 1999), and, therefore, the mutation rate does not necessarily accurately reflect the overall rate of gene inactivation. Furthermore, nearly all human tumors show an enhanced mutation rate or chromosomal instability (Lengauer et al. 1998). The total frequency of gene inactivation in …