Article Source: John Hopkins Medicine

Abstract: Two-thirds of the mutations that cause cancer may be due to random, unpredictable DNA copying “mistakes,” says the data released by the scientists from the Johns Hopkins Kimmel Cancer Center in Baltimore, MD. These errors are reported to occur regardless of lifestyle and environmental factors.


Complete Article:

A new study by scientists at the Johns Hopkins Kimmel Cancer Center has provided an evidence that random, unpredictable DNA copying typos are the reason for nearly two-thirds of the mutations that cause cancer. Their research was based on a novel mathematical model consisting DNA sequencing and epidemiologic data from around the world.

Everyone knows that we must avoid environmental factors such as smoking to reduce our risk of getting cancer. But only a few know that each time a normal cell divides and copies its DNA to produce two new cells, it makes multiple mistakes. “These copying mistakes are a potent source of cancer mutations that historically have been scientifically undervalued, and this new work provides the first estimate of the fraction of mutations caused by these mistakes,” says Cristian Tomasetti, Ph.D., assistant professor of biostatistics at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health.

“We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations. However, many people will still develop cancers due to these random DNA copying errors, and better methods to detect all cancers earlier, while they are still curable, are urgently needed,” says Bert Vogelstein, M.D., co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center.

The findings of the new study have been described by Tomasetti and Vogelstein in a report published on March 24 in the journal Science.

The conclusions of the study are in accord with epidemiologic studies showing that approximately 40 percent of cancers can be prevented by avoiding unhealthy environments and lifestyles. But among the factors driving the new study, the researchers say that people who follow all the rules of healthy living — nonsmoker, healthy diet, healthy weight, little or no exposure to known carcinogens — and have no family history of the disease also often get stricken by cancer which raises the pained question “Why me?”

The duo, Tomasetti and Vogelstein believe the answer to the above question lies in the random DNA copying errors. Though the current and future efforts to lessen known environmental risk factors will surely impact on cancer incidence in the U.S. and abroad, but the researchers say that the new study confirms that too little scientific attention is given to early detection strategies that would address a large number of cancers caused by random DNA copying errors. And for the same reason, Vogelstein says, “These cancers will occur no matter how perfect the environment.”

In a previous study authored by Tomasetti and Vogelstein in the Jan. 2, 2015, issue of Science, the pair reported that DNA copying errors could explain why certain cancers in the U.S., such as those of the colon, occur more commonly than other cancers, such as brain cancer.

In the new study, the researchers addressed a different question: What fraction of mutations in cancer is due to these DNA copying errors?

For answering the question, the scientists took a close look at the mutations that drive abnormal cell growth among 32 cancer types (Supplemental Materials, Table S6). They developed a new mathematical model using DNA sequencing data from The Cancer Genome Atlas and epidemiologic data from the Cancer Research UK database.

The researchers say that generally, two or more critical gene mutations are necessary for cancer to occur. These mutations can be a result of a random error during DNA copying errors, the environment or inherited genes. Having the knowledge, the pair, Tomasetti and Vogelstein used their mathematical model to show, for example, that when critical mutations in pancreatic cancers are added together, 77 percent of them are due to random DNA copying errors, 18 percent due to environmental factors, such as smoking, and the remaining 5 percent due to heredity.

The study also reported that, in other cancer types, like prostate, brain or bone, more than 95 percent of the mutations occur due to random copying errors. A difference was noted in lung cancer in which environmental factor, particularly smoking caused 65 percent of all the mutations while errors in DNA copying resulted in only 35 percent of mutations. Inherited factors are not known to play a role in lung cancers.

On looking across all 32 cancer types studied, the researchers estimate that 66 percent of cancer mutations occur due to copying errors, 29 percent can be attributed to lifestyle or environmental factors, and the remaining 5 percent are inherited.

The study carried out by Tomasetti and Vogelstein in 2015 created vigorous debate from scientists who argued that their previously published analysis did not include breast or prostate cancers, and it reflected only cancer incidence in the United States.

However, Tomasetti and Vogelstein now report a similar pattern worldwide, supporting their conclusions. According to them, the more cells divide, the higher the potential for so-called copying mistakes in the DNA of cells in an organ. To support the statement, they compared total numbers of stem cell divisions with cancer incidence data collected by the International Agency for Research on Cancer on 423 registries of cancer patients from 68 countries other than the U.S., representing 4.8 billion people, or more than half of the world’s population. This time, the researchers were also able to include data from breast and prostate cancers. They found a strong correlation between cancer incidence and normal cell divisions among 17 cancer types, regardless of the countries’ environment or stage of economic development.

According to Tomasetti, these random DNA copying errors will only get more important as societies face aging populations, prolonging the opportunity for our cells to make more and more DNA copying errors. And since these errors are a major reason for most cancers, Vogelstein says that people with cancer who have avoided known risk factors should be comforted by their findings. “It’s not your fault,” says Vogelstein. “Nothing you did or didn’t do was responsible for your illness.”

Journal Reference:

Cristian Tomasetti, Lu Li, Bert Vogelstein. Stem cell divisions, somatic mutations, cancer etiology, and cancer preventionScience, 2017 DOI: 10.1126/science.aaf9011