Behind the science: Hopkins oncologists discuss their research on the random mutations that cause cancer

In a new study examining cancer databases around the world, Johns Hopkins scientists in the Kimmel Cancer Center have discovered that random, unpredictable DNA copying "mistakes" account for nearly two-thirds of the mutations that cause cancer. Early detection of cancer, they say, remains a critical goal of cancer research.

Image caption: Cristian Tomasetti (left) and Bert Vogelstein

"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, co-director of the Ludwig Center at the Kimmel Cancer Center, who conducted the research along with Cristian Tomasetti, an assistant professor in the Bloomberg School of Public Health's Department of Biostatistics.

For the study, the scientists took a close look at the mutations that drive abnormal cell growth among 32 cancer types. They found that in cancer types such as prostate, brain, or bone, more than 95 percent of the mutations are caused by random copying errors. In some cancers, they found a greater influence of environmental factors, such as in lung cancer, in which 65 percent of all the mutations are due to environmental and lifestyle factors—mostly smoking—and 35 percent are due to DNA copying errors.

To help explain their work, the scientists discussed their methods and findings.

What is the take-home message of this research?

Random, unpredictable DNA "mistakes" account for nearly two-thirds of the mutations in cancers. These mutations occur as a result of DNA copying errors made when normal cells divide.

What causes such random DNA copying 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.

How does the environment and heredity play a role in cancer?

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.

So 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. We believe that more research to find better ways to detect cancers earlier is urgently needed.

Many people will develop cancer no matter how perfect their behaviors are because of random copying errors. These people should not feel guilty about getting cancer—there is nothing they could have done to avoid it. The mutations in virtually all childhood cancers are due to random copying errors, and there's nothing anyone could have done to prevent it.

What kind of data helped you determine the fraction of mutations caused by random DNA copying errors, environment, and heredity?

There were multiple sources of information. In pancreatic cancer, for example, we analyzed genomic sequencing data compiled by The Cancer Genome Atlas. We found that smokers with pancreatic cancer have 16 percent more mutations in their tumors than non-smokers with cancer. We also took into account epidemiologic data on diet and other environmental influences. Finally, we considered the role of inherited factors that have been discovered through studies of families with a predisposition to this disease.

Then, we developed a new mathematical model to determine the fraction of cancer mutations that occur as a result of random DNA copy errors compared with environmental or inherited factors. We found that 66 percent of the total mutations are caused by random DNA copy errors, 29 percent are caused by environmental or lifestyle factors, and the remaining 5 percent are hereditary.

How does this new study compare to the previous research you published in January 2015?

In the 2015 study, we compared cancer incidence in the U.S. to the total number of cell divisions in the organs in which the cancers occurred. This allowed us to explain why certain cancers, such as those of the colon, occur more commonly than other cancers, such as those in the brain. That study suggested that copying errors might play a more important role in cancer than previously believed. However, we did not determine what fraction of the mutations in cancers were due to these copying errors.

In the new study, the researchers we were able to determine the fraction of mutations due to random copying errors in 32 cancer types. Instead of data on cell divisions, we used a new mathematical model to analyze DNA sequencing and epidemiologic data.

We also addressed whether the correlations we found in 2015 between cancer incidence and cell divisions were universal rather than confined to the U.S. For this purpose, we compared stem cell division rates with cancer incidence data in 68 countries other than the U.S, representing 4.8 billion people, more than half of the world's population. We also included data on breast and prostate cancer, which were not included in the 2015 study. We found the same striking relationship between cell division and cancer incidence in various organs, regardless of the country and its environment.