Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention
Of equal importance, these studies provide a well-defined, molecular explanation for the large and apparently unpreventable component of cancer risk that has long puzzled epidemiologists. It is, of course, possible that virtually all mutations in all cancers are due to environmental factors, most of which have simply not yet been discovered. However, such a possibility seems inconsistent with the exhaustively documented fact that about three mutations occur every time a normal cell divides and that normal stem cells often divide throughout life.
Our studies complement, rather than oppose, those of classic epidemiology. For example, the recognition of a third, major factor (R) underlying cancer risk can inform epidemiologic studies by pointing to cancers that cannot yet be explained by R (i.e., those with too few stem cell divisions to account for cancer incidence). Such cancer types seem particularly well suited for further epidemiologic investigation. Additionally, R mutations appear unavoidable now, but it is conceivable that they will become avoidable in the future. There are at least four sources of R mutations in normal cells: quantum effects on base pairing (30), mistakes made by polymerases (31), hydrolytic deamination of bases (32), and damage by endogenously produced reactive oxygen species or other metabolites (33). The last of these could theoretically be reduced by the administration of antioxidant drugs (34). The effects of all four could, in principle, be reduced by introducing more efficient repair genes into the nuclei of somatic cells or through other creative means.
As a result of the aging of the human population, cancer is today the most common cause of death in the world (12). Primary prevention is the best way to reduce cancer deaths. Recognition of a third contributor to cancer—R mutations—does not diminish the importance of primary prevention but emphasizes that not all cancers can be prevented by avoiding environmental risk factors (Figs. 2 and 3). Fortunately, primary prevention is not the only type of prevention that exists or can be improved in the future. Secondary prevention, i.e., early detection and intervention, can also be lifesaving. For cancers in which all mutations are the result of R, secondary prevention is the only option.
Stem cell divisions, somatic mutations, cancer etiology, and cancer preventionCristian Tomasetti, Lu Li, Bert Vogelstein
Materials/Methods, Supplementary Text, Tables, Figures, and/or References
- Materials and Methods
- Figs. S1 and S2
- Captions for tables S1 to S6
- Cumulative risk and correlation data for age interval zero to75.
- Cumulative risk and correlation data for age interval zero to 80.
- Cumulative risk and correlation data for age interval zero to 85.
- Cumulative risk and correlation data for the age interval zero to 85+.
- Epidemiological cancer data.
- Proportion of driver gene mutations attributable to E, H, and R.
Materials and Methods
Figs. S1 and S2
Tables S1 to S6