Cancer occurs in cells which, due to mutations, are losing their tight regulation for controlled cell division and undergo uncontrolled proliferation resulting in tumor development and/or metastases. What is the origin of these cancer-driving mutations?
A recent article published in top ranked scientific journal, Science, addressed the contribution of random mutations for cancer development by analyzing cancer incidence among 4.8 billion people (two-thirds of the world’s population) in 69 countries, among 17 cancer types.
There are three possible origins for cancer-driving mutations: Heredity (H), Environment (E) or random mutations accumulated during DNA replication (R).The role of genetics in developing cancer is supported by studies on twins and on cancer predisposition mutations. The environmental effect is also well documented, as evident from epidemiological studies on smoking, exposure to sunlight, and etc. This is the major area targeted for cancer prevention. After observing that the risk of cancer in different tissues correlates with the number of normal stem cell division in these tissues, researchers hypothesized that there may be a possible contribution of random errors (R) in cancer development.
There is a statistical chance for random mutations during replication of genetic material before each cell division, and as documented, three mutations on average occur during each replication. A randomly mutated sequence carrying genetic information for a gene involved in cell cycle regulation may drive a specific cell to tumorigenic behavior. The hypothesis of a correlation between the number of cell divisions and cancer was previously supported by studies in mice.
It is challenging to define which of the factors above (H, E, or R) contribute to cancer phenotype in a patient – sometimes a single factor and other times an accumulation of several changes is required to trigger the disease.
In a new study, the role of R mutations in cancer development was evaluated. The assumption is that the number of random mutations will be the same in the same age group independent of H and E factors. The study evaluated cancer incidence among 4.8 billion people (two-thirds of the world population) in 69 countries, representing a variety of environmental conditions. The incidences of cancer were determined using information from 423 cancer registries made available by International Agency for Research on Cancer. 17 types of cancer were evaluated. Strong statistically significant correlations between stem cells divisions and incidence of cancer were observed in all countries, with the median correlation of 0.8. The data indicates that the larger the age range considered the higher the correlation – 0.8 in (0-85+) as compared to 0.75 in age group (0-75).
Researchers were interested in identifying mutations that contribute to the R factor. To do so, the adenocarcinoma of the lung was selected as a model. Epidemiological studies have shown that 90% of the lung cancer adenocarcinomas are preventable, with the highest correlation to tobacco smoking. Researchers then compared rate of mutations (by genome sequencing) of patients who were exposed to tobacco with patients free from smoking and determined contribution of smoking on mutation rate. Out of 20 tested patients, in 18 cases the driving mutations were attributed to tobacco, an environmental factor. Additional mathematical calculations and statistical analysis revealed that about 35% of lung cancer mutations are due to factors unrelated to E and H and are caused by R factor. The percentages vary for other cancer types; R factor attributed to 77% of pancreatic and 95% of prostate cancers. The recognition of the third factor, R, as a significant contributor to cancer development is important for understanding malignancies, such as prostate cancer, for which there is no or a low contribution of E or H factors.
Most cancers require more than one mutation to trigger the disease, therefore if one mutation is contributed by R factor and the second by E, the disease may be preventable by avoiding environmental risk. Study data consistent with the US Center of Disease Control and Prevention estimates that 21% of cancer death could be prevented by proper lifestyle and diet.
The knowledge of contribution of random mutations originated by stem cell divisions is also important for epidemiologists to identify cancers which cannot be attributed to R (eg. brain, bone, tissue cancers with low cell division rates), in order to carry out more epidemiologic studies.
This study opens new avenues for drug development aimed at correcting/avoiding errors in replication. As the human population ages, cancer is a major cause of death, and recognition of R factor emphasizes the importance of preventive actions combined with early detection for the development of novel anticancer drugs.
Written By: Bella Groisman, PhD