Mutations Resulting from DNA Replication Errors Play a Role in Cancer Development

DNA replication errors have been identified as a third major factor contributing to cancer development, according to a study recently published in Science. Study results provided “a well-defined, molecular explanation for the large and apparently unpreventable component of cancer risk that has long puzzled epidemiologists,” the authors wrote.

Globally, cancer is the number one cause of death. Extensive research has confirmed the roles of heredity (H) and the environment (E) in causing driver mutations, which are mutations that promote cancer development by providing a growth advantage to cancer cells. More recently, it has been hypothesized that DNA replication errors (R) also play a major role in cancer development.

In normal stem cells, 3 mutations occur per cell division. Results from a previous mouse model study suggested a relationship between cell division number and cancer risk in various organs. Because cell division is a fundamental biological process in humans, mutations due to R factors are distributed relatively evenly across the human population, unlike the widely variable distribution of mutations due to E or H factors.

Study Design and Results

For the current study, the authors analyzed 423 cancer registries. They determined the incidence of 17 cancer types in 69 countries; cancers for which stem cell data were available were included in the analysis. The authors then calculated the correlation between normal stem cell divisions and lifetime cancer risk across age groups (0—85+, 0–85, 0–80, and 0–75 years).

All countries had strong and statistically significant correlations, with an overall median correlation of 0.80. In almost 90% of countries, the correlation was greater than 0.70 in the 0—85+ age group. Generally, the correlation value increased as the age group size increased.

The high correlations across all countries surprised the authors, given the amount of data indicating wide global variations in exposure to environmental mutagens and associated cancer incidences. To investigate these surprising results, the authors calculated the percentage of driver mutations due to E, H, and R factors for various cancers.

Analytical Modeling

To date, accurately determining the individual contributions of E, H, and R factors to cancer development has been challenging. To address this challenge, the authors devised an analytical approach in which driver mutations not due to E or H factors were presumed to be due to R factors.

First, they developed a hypothetical example in which a sizeable percentage of driver mutations (40%) were due to R factors, even when E factors were dominant. They then calculated the percentage of driver mutations due to R factors for real-life cancers in which E factors play variably sized roles in cancer development.

• Lung adenocarcinoma: Major E factor role; 35% of driver mutations due to R factors
• Pancreatic adenocarcinoma: Minor E factor role; 77% of driver mutations due to R factors
• Prostatic adenocarcinoma: Virtually no E factor role; 95% of driver mutations due to R factors

Following this analytical approach, the authors calculated the percentage of driver mutations due to E, H, and R factors for 32 cancer types reported in the Cancer Research UK database. For males and females, the percentages were as follows:

• E factors: 29%
• H factors: 5%
• R factors: 66%

Conclusions

Taken together, study results “have important ramifications for understanding the root cause of cancer as well as for minimizing deaths from this disease,” the authors wrote. Despite the identification of DNA replication errors as a third major contributor to cancer development, the authors emphasized the continued importance of cancer prevention strategies, such as health education, reduced exposure to environmental mutagens, and cancer screening.

Dr. JoAnna Pendergrass received her Doctor of Veterinary Medicine degree from the Virginia-Maryland College of Veterinary Medicine. Following veterinary school, she completed a postdoctoral fellowship at Emory University’s Yerkes National Primate Research Center. Dr. Pendergrass is the founder and owner of JPen Communications, a medical communications company.