Two thirds of the mutations that cause cancer may be due to random, unpredictable DNA copying "mistakes," according to scientists from the Johns Hopkins Kimmel Cancer Center in Baltimore, MD. These errors are reported to occur regardless of lifestyle and environmental factors.

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Most mutations that cause cancer result from random DNA copying errors that occur when cells divide.

It is not entirely understood why some people develop cancer while others do not. There are lifestyle and environmental risk factors that make a person more likely to develop cancer, such as smoking, drinking alcohol, obesity, and exposure to harmful chemicals.

While these risk factors can be avoided to lower the risk of cancer, the majority of cancer cases occur in people with no known risk factors and no family history of the disease.

For people that try to actively decrease their chances of disease by living a healthy lifestyle and avoiding known risk factors and yet still develop cancer, they may question what they are doing wrong. Bert Vogelstein, co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center says: "It's not your fault. Nothing you did or didn't do was responsible for your illness."

Even with the best health intentions, cancer may still develop due to mistakes that crop up when cells divide to form new cells.

Early detection strategies may tackle cancers caused by copying errors

The team at the Johns Hopkins Kimmel Cancer Center conducted a study to find out what fraction of mutations in cancer DNA copying errors are responsible for. Their findings were published in the journal Science.

"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," 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.

"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," he adds.

"We need to continue to encourage people to avoid environmental agents and lifestyles that increase their risk of developing cancer mutations," says Vogelstein. "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."

Tomasetti and Vogelstein's research agrees with previous studies that show that around 40 percent of cancers could be prevented "by avoiding unhealthy lifestyles and environments."

The researchers say that while efforts to reduce environmental risk factors will have a significant impact on cancer incidence, the new research highlights that there is little attention given to early cancer detection strategies that would tackle the considerable number of cancers that are caused by DNA copying errors. "These cancers will occur no matter how perfect the environment," explains Vogelstein.

Mutations in cancer due to DNA copying mistakes investigated

Mutations that are behind abnormal cell growth in 32 types of cancer were observed. According to the researchers, it typically takes two or more critical gene mutations to cause cancer. These mutations can be due to inherited genes, the environment, or random DNA copying errors.

The team developed a new mathematical model using DNA sequencing data from The Cancer Genome Atlas and epidemiologic data from the Cancer Research UK database to find out what fraction of cancer mutations are due to DNA copying mistakes.

Using the mathematical model, Tomasetti and Vogelstein could add together the critical mutations in each of the 32 cancer types and determine what percentage of mutations were due to DNA copying errors, the environment, and hereditary factors. For example, for pancreatic cancer, when the critical mutations were added together, 77 percent were a result of random DNA copying errors, 18 percent were due to environmental factors, and 5 percent down to heredity.

In cancers of the bone, brain, and prostate, more than 95 percent of mutations were the result of random DNA copying mistakes.

In contrast, lung cancer painted a different picture: 65 percent of mutations were a result of environmental factors, predominantly smoking. The other 35 percent of mutations were attributed to copying errors. It is not thought that inherited factors have a part in the development of lung cancers.

Overall, the team estimated that across the 32 types of cancer, 66 percent of cancer mutations are due to random DNA copying mistakes, 29 percent result from lifestyle and environmental factors, and the remaining 5 percent are down to hereditary factors.

Strong correlation between cancer incidence and normal cell division

Tomasetti, Vogelstein, and colleagues likened the reasons that mutations occur to why "typos" happen during the typing of a 20-volume book. Typos often happen when people are tired, representing environmental factors, or if a key on the keyboard is missing or stuck, representing inherited factors. Some typographical errors just randomly happen, which represents DNA copying errors.

"You can reduce your chance of typographical errors by making sure you're not drowsy while typing and that your keyboard isn't missing some keys. But typos will still occur because no one can type perfectly. Similarly, mutations will occur, no matter what your environment is, but you can take steps to minimize those mutations by limiting your exposure to hazardous substances and unhealthy lifestyles."

Bert Vogelstein

The researchers compared the total numbers of stem cell divisions with worldwide cancer incidence data. They found a strong correlation between cancer incidence and normal cell division in 17 types of cancer, despite the state of the countries' environment or economic development.

The more cells divide, the higher is the likelihood that DNA copying errors will occur in cells of an organ. These errors will only get more important as "societies face aging populations," among which cells are given the opportunity to produce an increasing amount of copying errors, concludes Tomasetti.

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