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New Study Finds Most Cancer Mutations Due to Random DNA-Copying Errors

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Key Points

  • Looking across all 32 cancer types studied, the researchers estimate that 66% of cancer mutations result from copying errors, 29% can be attributed to lifestyle or environmental factors, and the remaining 5% are inherited.
  • Drs. Tomasetti and Vogelstein used their mathematic 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% to heredity. In other cancer types, such as those of the prostate, brain, or bone, more than 95% of the mutations are due to random copying errors.
  • Lung cancer, they note, presents a different picture: 65% of all the mutations are due to environmental factors (mostly smoking) and 35% are due to DNA-copying errors. Inherited factors are not known to play a role in lung cancers.

Johns Hopkins Kimmel Cancer Center scientists report data from a new study providing evidence that random, unpredictable DNA copying “mistakes” account for nearly two-thirds of the mutations that cause cancer. Their research is grounded on a novel mathematic model based on DNA sequencing and epidemiologic data from around the world. Tomasetti and Vogelstein conducted the new study described in a report published March 24 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,” said Cristian Tomasetti, PhD, 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.”

“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,” said Bert Vogelstein, MD, Co-Director of the Ludwig Center at the Johns Hopkins Kimmel Cancer Center.

Current and future efforts to reduce known environmental risk factors, the researchers said, will have major impacts on cancer incidence in the United States 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.

“These cancers will occur no matter how perfect the environment,” said Dr. Vogelstein.

In a previous study authored by Drs. Tomasetti and Vogelstein in Science, the pair reported that DNA-copying errors could explain why certain cancers in the United States, 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?

Study Findings

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 mathematic 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, Drs. Tomasetti and Vogelstein used their mathematic 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% to heredity.

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

Lung cancer, they note, presents a different picture: 65% of all the mutations are due to environmental factors (mostly smoking) and 35% 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% of cancer mutations result from copying errors, 29% can be attributed to lifestyle or environmental factors, and the remaining 5% are inherited.

Earlier Criticism

Drs. 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, Drs. 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 United States, 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.

Dr. Tomasetti said 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, Dr. Vogelstein said that people with cancer who have avoided known risk factors should be comforted by their findings. “It’s not your fault,” said Dr. Vogelstein. “Nothing you did or didn’t do was responsible for your illness.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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