Study: Two-Thirds of Cancers Are Caused by Random Genetic Mistakes

John Hopkins experts call for early-detection strategies

A new study conducted at the Johns Hopkins Kimmel Cancer Center has provided evidence that random and unpredictable DNA copying “mistakes” account for nearly two-thirds of the mutations that cause cancer.

“It is well known that we must avoid environmental factors, such as smoking, to decrease our risk of getting cancer. But it is not as well known that each time a normal cell divides and copies its DNA to produce two new cells, it makes multiple mistakes,” said Christian Tomasetti, PhD. “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.”

Bert Vogelstein, MD, added: “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.”

Drs. Tomasetti and Vogelstein conducted the new study, which was published in Science.

The researchers say their conclusions are in accord with epidemiologic studies, which showed that approximately 40% of cancers can be prevented by avoiding unhealthy environments and lifestyles. But the new study also shows that cancer often strikes people who follow all of the rules of healthy living—no smoking, a healthy diet and weight, little or no exposure to known carcinogens—and have no family history of the disease, prompting the pained question, “Why me?”

Drs. Tomasetti and Vogelstein believe the answer to that question rests in random DNA copying errors.

Current and future efforts to reduce known environmental risk factors, they say, will have major effects on the cancer incidence in the U.S. and abroad. But they say the new study confirms that too little scientific attention has been given to early-detection strategies that would address the large number of cancers caused by random DNA copying errors.

In a 2015 study, also published in Science, the researchers 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, they addressed a different question: What fraction of mutations in cancer is due to these DNA copying errors?

To answer this question, they looked at the mutations that drive abnormal cell growth among 32 cancer types. They then developed a new mathematical model using DNA sequencing data from the Cancer Genome Atlas and epidemiologic data from the Cancer Research UK database.

According to the researchers, it generally takes two or more critical gene mutations for cancer to occur. These mutations can be due to random DNA copying errors, to the environment, or to inherited genes. Knowing this, Drs. Tomasetti and Vogelstein used their mathematical model to show, for example, that when critical mutations in pancreatic cancers are added together, 77% of them are due to random DNA copying errors; 18% to environmental factors, such as smoking; and the remaining 5% percent to heredity. In other cancers, such as those of the prostate, brain, or bone, more than 95% of the mutations are due to random copying errors.

Lung cancer, the investigators note, presents a different picture: 65% of all mutations are due to environmental factors, mostly smoking, and 35% of mutations are due to DNA copying errors. Inherited factors are not known to play a role in lung cancers.

Drs. Tomasetti and Vogelstein reasoned that the more cells divide, the higher the potential for copying mistakes in the DNA of cells in an organ. They compared the total numbers of stem cell divisions with cancer incidence data collected by the International Agency for Research on Cancer from 68 countries, representing 4.8 billion people, or more than half of the world’s population. The investigators found a strong correlation between cancer incidence and normal cell division among 17 cancer types, regardless of the countries’ environment or stages of economic development.

Source: Johns Hopkins Kimmel Cancer Center; March 23, 2017.