DNA Replication Errors To Blame For Most Cancer Mutations

Random, unpredictable DNA copying mistakes account for nearly two-thirds of the mutations that cause cancer, report scientists from Johns Hopkins. The research is based on a unique mathematical model derived from DNA sequencing and epidemiologic data from around the world.

Cristian Tomasetti, Ph.D., assistant professor of biostatistics at the Johns Hopkins Kimmel Cancer Center and the Johns Hopkins Bloomberg School of Public Health, explains:

“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. 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.”

The researchers say their conclusions 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, say the researchers, is that cancer often strikes 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, prompting the pained question “Why me?”

Early Detection Is Key

Bert Vogelstein, M.D., co-director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center, says:

“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.”

Tomasetti and Vogelstein believe the answer to that “Why me?” question rests in random DNA copying errors.

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

A previous study by Tomasetti and Vogelstein in 2015 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 are due to these DNA copying errors?

Critical Gene Mutations

To answer this question, the scientists took a close look at the mutations that drive abnormal cell growth among 32 cancer types. They 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. In a person, these mutations can be due to random DNA copying errors, the environment or inherited genes.

Knowing this, 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 to environmental factors, such as smoking, and the remaining 5 percent to heredity.

DNA replication cancer causes

Mutations attributable to environmental factors (right), DNA replication (center) and heredity (left) in the UK female population. Credit: C. Tomasetti et al,. Science (2017)

For other cancer types, such as those of the prostate, brain or bone, more than 95 percent of the mutations are due to random copying errors.

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

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

Worldwide Pattern

The scientists say their approach is akin to attempts to sort out why “typos” occur when typing a 20-volume book: being tired while typing, which represents environmental exposures; a stuck or missing key in the keyboard, which represent inherited factors; and other typographical errors that randomly occur, which represent 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,” says Vogelstein. “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.”

Tomasetti and Vogelstein’s 2015 study 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. They reasoned that the more cells divide, the higher the potential for so-called copying mistakes in the DNA of cells in an organ.

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 prostate and breast 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.

Tomasetti says 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 because these errors contribute to a large fraction of cancer, 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.”

Random DNA Replication Errors

Human cells are constantly regenerating. The body makes new cells billions of times throughout a person’s lifetime.

Each time a cell divides to make a new cell, its DNA is copied and, on average, makes three random mistakes. Most of these mistakes are harmless, but a small fraction of them occur in a gene that will kick-start a cell’s uncontrollable replication, leading to cancer.

In other words, most of the mutations that occur when our cells divide cause no damage. Occasionally, a mutation occurs in a cancer gene, leading to the disease.

Certain lifestyles or environmental exposures — smoking and obesity — also cause mutations in DNA. This is why it is so important to avoid such lifestyles and environments. In addition, some people have altered genes that “run” in families, such as BRCA-1 and BRCA-2, that are linked to very high risk of breast and other cancers.

Does this mean there’s nothing we can do to prevent cancer deaths?

Not at all. Clearly, some types of the disease, such as lung cancer, are heavily influenced by environmental factors.

So maintaining a healthy weight and avoiding exposure to known carcinogens, such as smoking, are critical for preventing deaths from these cancer types. It’s estimated that approximately 40 percent of cancers can be prevented if people avoided these risk factors, and our results are in accord with those estimates.

Early detection and intervention can prevent many cancer deaths. Detecting cancers earlier, while they are still curable, can save lives regardless of what caused the mutation. More research to find better ways to detect cancers earlier is urgently needed.

Cristian Tomasetti, Lu Li, Bert Vogelstein
Stem cell divisions, somatic mutations, cancer etiology, and cancer prevention
Science  24 Mar 2017: Vol. 355, Issue 6331, pp. 1330-1334 DOI: 10.1126/science.aaf9011

Top Image: University of Michigan School of Natural Resources & Environment CC-BY

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