Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention

Abstract

Cancers are caused by mutations that may be inherited, induced by environmental factors, or result from DNA replication errors (R). We studied the relationship between the number of normal stem cell divisions and the risk of 17 cancer types in 69 countries throughout the world. The data revealed a strong correlation (median = 0.80) between cancer incidence and normal stem cell divisions in all countries, regardless of their environment. The major role of R mutations in cancer etiology was supported by an independent approach, based solely on cancer genome sequencing and epidemiological data, which suggested that R mutations are responsible for two-thirds of the mutations in human cancers. All of these results are consistent with epidemiological estimates of the fraction of cancers that can be prevented by changes in the environment. Moreover, they accentuate the importance of early detection and intervention to reduce deaths from the many cancers arising from unavoidable R mutations.

Fig. 1. Correlations between stem cell divisions and cancer incidence in different countries

For each country, the correlation between the number of stem cell divisions in 17 different tissues and the lifetime incidence of cancer in those tissues was calculated. This resulted in correlation coefficients, which were grouped and plotted into a histogram. In this histogram, the x axis represents the correlation coefficients and the y axis represents the number of countries with the corresponding correlation coefficient. For example, there were seven countries in which the correlation between the number of stem cell divisions and cancer incidence was between 0.82 and 0.83; these seven countries are represented by the tallest green bar in the histogram. The median correlation coefficient over all countries was 0.8. The black line represents the density for the observed distribution of the correlation coefficient among different countries.

Fig. 2. Mutation etiology and cancer prevention in a hypothetical scenario and in real life

Patients exposed to environmental factors, such as cigarette smoke, are surrounded by a cloud. The driver gene mutations calculated to be attributable to environmental (E), hereditary (H), and replicative (R) factors are depicted as gray, blue (containing an “H”), and yellow circles, respectively. For simplicity, each cancer patient is shown as having three driver gene mutations, but the calculations are based on percentages. Thus, if there are three driver gene mutations in a cancer and R accounts for 33% of them, then one mutation is assigned to R. (A) A hypothetical scenario consisting of an imaginary place, Planet B, where all inherited mutations have been corrected and where the environment is perfect. A powerful mutagen is then introduced that increases cancer risk 10-fold, so that 90% of cancers on this planet are preventable. In some individuals on this planet, all mutations are due to E, whereas in the two individuals in the bottom right corner, all are due to R. In the other patients, only some of the somatic mutations in their tumors result from E. Even though 90% of the cancers are preventable by eliminating the newly introduced mutagen, 40% of the total driver gene mutations are due to R. (B to D) Real-life examples of mutation etiology and cancer prevention. (B) The approximate proportion of driver gene mutations in lung adenocarcinomas that are due to environmental versus nonenvironmental factors are shown as gray and yellow circles, respectively. Even though 89% of lung adenocarcinomas are preventable (17) by eliminating E factors, we calculate that 35% (95% CI: 30 to 40%) of total driver gene mutations are due to factors unrelated to E or H and presumably are due to R. (C) The approximate proportion of driver gene mutations in pancreatic ductal adenocarcinomas, in which hereditary factors are known to play a role. It has been estimated that ~37% (17) of pancreatic ductal adenocarcinomas are preventable, but at most 18% and 5% of the driver gene mutations in these cancers are estimated to be due to E and H, respectively. The remaining 77% (95% CI: 82 to 94%) of the total driver gene mutations are due to factors other than E or H, presumably R. (D) The approximate proportion of driver gene mutations in prostate cancers, in which environmental factors are thought to play essentially no role (17) and hereditary factors account for 5 to 9% of cases (see supplementary materials). None of these cancers are preventable, and less than 5% of the driver mutations in these cancers are due to E or H. The remaining 95% of the total driver gene mutations are due to factors other than E or H, presumably R. [Image: The Johns Hopkins University]

Fig. 3. Etiology of driver gene mutations in women with cancer

For each of 18 representative cancer types, the schematic depicts the proportion of mutations that are inherited, due to environmental factors, or due to errors in DNA replication (i.e., not attributable to either heredity or environment). The sum of these three proportions is 100%. The color codes for hereditary, replicative, and environmental factors are identical and span white (0%) to brightest red (100%). The numerical values used to construct this figure, as well as the values for 14 other cancer types not shown in the figure, are provided in table S6. B, brain; Bl, bladder; Br, breast; C, cervical; CR, colorectal; E, esophagus; HN, head and neck; K, kidney; Li, liver; Lk, leukemia; Lu, lung; M, melanoma; NHL, non-Hodgkin lymphoma; O, ovarian; P, pancreas; S, stomach; Th, thyroid; U, uterus. [Image: The Johns Hopkins University]