An estimated 1016 cell divisions occur in a normal human body in the course of a typical lifetime; in a mouse, with its smaller number of cells and its shorter lifespan, the number is about 1012. Even in an environment that is free of mutagens, mutations would occur spontaneously at an estimated rate of about 10–6 mutations per gene per cell division—a value set by fundamental limitations on the accuracy of DNA replication and repair (see pp. 237–238). Thus, in a typical lifetime, every single gene is likely to have undergone mutation on about 1010 separate occasions in a human, or on about 106 occasions in a mouse. Among the resulting mutant cells, we might expect a large number that have sustained deleterious mutations in genes that regulate cell growth and division, causing the cells to disobey the normal restrictions on cell proliferation. From this point of view, the problem of cancer seems to be not why it occurs, but why it occurs so infrequently.
Clearly, if a mutation in a single gene were enough to convert a typical healthy cell into a cancer cell, we would not be viable organisms. Many lines of evidence indicate that the development of a cancer typically requires that a substantial number of independent, rare genetic and epigenetic accidents occur in the lineage that emanates from a single cell. One such indication comes from epidemiological studies of the incidence of cancer as a function of age (Figure 20–6). If a
Figure 20–5 The translocation between chromosomes 9 and 22 responsible for chronic myelogenous leukemia.
The normal structures of chromosomes 9 and 22 are shown at the left. When a translocation occurs between them at the indicated site, the result is the abnormal pair at the right. The smaller of the two resulting abnormal chromosomes (22q–) is called the Philadelphia chromosome, after the city where the abnormality was first recorded.
Figure 20–6 Cancer incidence as a function of age. The number of newly 180 diagnosed cases of colon cancer in women in England and Wales in 1 year is plotted as a function of age at diagnosis, relative to the total number of individuals in each age group. The incidence of cancer rises steeply as a function of age. If only a single mutation were required to trigger the cancer and this mutation had an equal chance of occurring at any time, the incidence of this cancer would be the same at all ages. Analyses of this type suggest that the development of a solid tumor instead requires five to eight independent accidents (“hits”) that occur randomly over time. This calculation incidence rate per 100,000 assumes that the mutation rate remains constant as a cancer evolves, where in fact it often increases (see p. 1097). (Data from C. Muir et al., Cancer
Incidence in Five Continents, Vol. V. Lyon: International Agency for Research on Cancer, 1987.) single mutation were responsible for cancer, occurring with a fixed probability per year, the chance of developing cancer in any given year of life should be indepen dent of age. In fact, for most types of cancer, the incidence rises steeply with age— as would be expected if cancer is caused by a progressive, random accumulation 20 of a set of mutations in a single lineage of cells.
As discussed later, these indirect arguments have now been confirmed by sys-0 tematically sequencing the genomes of the tumor cells from individual cancer patients and cataloging the mutations that they contain.