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New study finds that most cancer mutations are due to random DNA copying errors

Mar 23, 2017

A new study by Ludwig researchers at Johns Hopkins finds that random “mistakes” dividing cells make when copying their DNA account for nearly two-thirds of the mutations that cause cancer. It reaches this conclusion on the basis of a novel mathematical model that relies on DNA sequencing and epidemiologic data from around the world. Published in the current issue of Science, the study is led by Ludwig Johns Hopkins Co-director Bert Vogelstein and his colleague Cristian Tomasetti, an 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,” said Vogelstein.

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.

“This study highlights the high mutational burden that occurs during our lifetimes, even when best health practices are followed,” said Robert Strausberg, Executive Vice President for Research. “These findings underscore the importance of early detection technologies that are well suited to be a part of routine annual physical exams throughout a person’s life, such as the blood-based approaches under development at the Ludwig Center at Johns Hopkins.”

A previous paper authored by Tomasetti and Vogelstein in the Jan. 2, 2015, issue of Science argued that DNA copying errors could explain why certain cancers in the U.S., such as those of the colon, are more common than others, such as brain cancers. Some argued that the analysis did not include breast or prostate cancers and that it reflected cancer incidence exclusively in the United States.

In their new study, the authors included breast and prostate cancers and performed a variety of additional analyses that addressed a different question: What fraction of mutations in cancer are due to these DNA copying errors? To answer this question, the scientists took a close look at the mutations that drive abnormal cell growth in 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.

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 in stem cells, environmental factors 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.

In 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.

Tomasetti and Vogelstein reasoned that the more the stem cells of an organ divide, the higher the potential for errors in the DNA of cells in that organ. For this study, the research team compared total numbers of stem cell divisions with cancer incidence data collected by the International Agency for Research on Cancer from 423 registries of cancer patients from 68 countries other than the U.S. The researchers found a strong correlation between cancer incidence and normal cell divisions among 17 cancer types, regardless of where they occur.

The release from which this summary has been adapted can be found here.