Scientists from the Johns Hopkins Kimmel Cancer Center created a statistical model that measures the proportion of cancer incidence across many tissue types. Some tissues give rise to cancer in humans a million times more frequently than others. Although this has been recognised for more than a century, it has never been explained. However, in their work now the researchers show that the lifetime risk of cancers of many different types is strongly correlated with the total number of divisions of the normal self-renewing stem cells maintaining the tissue’s homeostasis.
The results suggest that only a third of the variation in cancer risk among tissues is attributable to environmental factors or inherited predispositions. The majority is due to “bad luck,” that is, random mutations arising during DNA replication in normal, noncancerous stem cells. This is important not only for understanding the disease but also for designing strategies to limit the mortality it causes.
Dr Bert Vogelstein, the Clayton Professor of Oncology at the Johns Hopkins University School of Medicine, co-director of the Ludwig Center at Johns Hopkins and an investigator at the Howard Hughes Medical Institute cautions that poor lifestyles can add to the bad luck factor in the development of cancer.
The implications of the model range from altering public perception about cancer risk factors to the funding of cancer research. "If two-thirds of cancer incidence across tissues is explained by random DNA mutations that occur when stem cells divide, then changing our lifestyle and habits will be a huge help in preventing certain cancers, but this may not be as effective for a variety of others," says biomathematician Cristian Tomasetti, PhD, an assistant professor of oncology at the Johns Hopkins University School of Medicine and Bloomberg School of Public Health. "We should focus more resources on finding ways to detect such cancers at early, curable stages," he adds.
Crunching the numbers to explain cancer
In a report on their statistical findings, published in Science, Tomasetti and Vogelstein say they came to their conclusions by searching the scientific literature for information on the cumulative total number of divisions of stem cells among 31 tissue types during an average individual's lifetime. Stem cells "self-renew," thus repopulating cells that die off in a specific organ.
It was well-known, Vogelstein notes, that cancer arises when tissue-specific stem cells make random mutations. The more these mutations accumulate, the higher the risk that cells will grow unchecked, a hallmark of cancer. The actual contribution of these random mutations to cancer incidence, in comparison to the contribution of hereditary or environmental factors, was not previously known, says Vogelstein.
To sort out the role of such random mutations in cancer risk, the Johns Hopkins scientists charted the number of stem cell divisions in 31 tissues and compared these rates with the lifetime risks of cancer in the same tissues among Americans. From this so-called data scatterplot, Tomasetti and Vogelstein determined the correlation between the total number of stem cell divisions and cancer risk to be 0.804. Mathematically, the closer this value is to one, the more stem cell divisions and cancer risk are correlated.
"Our study shows, in general, that a change in the number of stem cell divisions in a tissue type is highly correlated with a change in the incidence of cancer in that same tissue," says Vogelstein. One example, he says, is in colon tissue, which undergoes four times more stem cell divisions than small intestine tissue in humans. Likewise, colon cancer is much more prevalent than small intestinal cancer.
"You could argue that the colon is exposed to more environmental factors than the small intestine, which increases the potential rate of acquired mutations," says Tomasetti. However, the scientists saw the opposite finding in mouse colons, which had a lower number of stem cell divisions than in their small intestines, and, in mice, cancer incidence is lower in the colon than in the small intestine. They say this supports the key role of the total number of stem cell divisions in the development of cancer.
Using statistical theory, the pair calculated how much of the variation in cancer risk can be explained by the number of stem cell divisions, which is 0.804 squared, or, in percentage form, approximately 65%.
Finally, the research duo classified the types of cancers they studied into two groups. They statistically calculated which cancer types had an incidence predicted by the number of stem cell divisions and which had higher incidence. They found that 22 cancer types could be largely explained by the "bad luck" factor of random DNA mutations during cell division. The other 9 cancer types had incidences higher than predicted by "bad luck" and were presumably due to a combination of bad luck plus environmental or inherited factors.
"We found that the types of cancer that had higher risk than predicted by the number of stem cell divisions were precisely the ones you'd expect, including lung cancer, which is linked to smoking; skin cancer, linked to sun exposure; and forms of cancers associated with hereditary syndromes," says Vogelstein.
"This study shows that you can add to your risk of getting cancers by smoking or other poor lifestyle factors. However, many forms of cancer are due largely to the bad luck of acquiring a mutation in a cancer driver gene regardless of lifestyle and heredity factors. The best way to eradicate these cancers will be through early detection, when they are still curable by surgery," adds Vogelstein.
The scientists note that some cancers, such as breast and prostate cancer, were not included in the report because of their inability to find reliable stem cell division rates in the scientific literature. They hope that other scientists will help refine their statistical model by finding more precise stem cell division rates.
The research was funded by the Virginia and D. K. Ludwig Fund for Cancer Research, the Lustgarten Foundation for Pancreatic Cancer Research, the Sol Goldman Pancreatic Cancer Research Center, and the USA National Institutes of Health's National Cancer Institute.
Most types of cancer not due to “bad luck”
The International Agency for Research on Cancer (IARC), the World Health Organization’s specialised cancer agency, strongly disagrees with the conclusion of a scientific report on the causes of human cancer published in the journalScienceby Dr Cristian Tomasetti and Dr Bert Vogelstein.
The study, which has received widespread media coverage, compares the number of lifetime stem cell divisions across a wide range of tissues with lifetime cancer risk and suggests that random mutations (or “bad luck”) are “the major contributors to cancer overall, often more important than either hereditary or external environmental factors.”
For many cancers, the authors argue for a greater focus on the early detection of the disease rather than on prevention of its occurrence. If misinterpreted, this position could have serious negative consequences from both cancer research and public health perspectives.
IARC experts point to a serious contradiction with the extensive body of epidemiological evidence as well as a number of methodological limitations and biases in the analysis presented in the report. “We already knew that for an individual to develop a certain cancer there is an element of chance, yet this has little to say about the level of cancer risk in a population,” explains IARC Director Dr Christopher Wild. “Concluding that ‘bad luck’ is the major cause of cancer would be misleading and may detract from efforts to identify the causes of the disease and effectively prevent it.”
The past five decades of international epidemiological research have shown that most cancers that are frequent in one population are relatively rare in another and that these patterns vary over time. For example, oesophageal cancer is common among men in East Africa but rare in West Africa. Colorectal cancer, once rare in Japan, increased 4-fold in incidence in just two decades. These observations are characteristic of many common cancers and are consistent with a major contribution of environmental and lifestyle exposures, as opposed to genetic variation or chance (“bad luck”).
Furthermore, IARC experts identify several limitations in the report itself. These include the emphasis on very rare cancers (e.g. osteosarcoma, medulloblastoma) that together make only a small contribution to the total cancer burden. The report also excludes, because of the lack of data, common cancers for which incidence differs substantially between populations and over time. The latter category includes some of the most frequent cancers worldwide, for example those of the stomach, cervix, and breast, each known to be associated with infections or lifestyle and environmental factors.
Moreover, the study focuses exclusively on the United States population as a measure of lifetime risk. The comparison of different populations would have yielded different results.
Although it has long been clear that the number of cell divisions increases the risk of mutation and, therefore, of cancer, a majority of the most common cancers occurring worldwide are strongly related to environmental and lifestyle exposures. In principle, therefore, these cancers are preventable; based on current knowledge, nearly half of all cancer cases worldwide can be prevented. This is supported in practice by rigorous scientific evidence showing decreases in cancer incidence after preventive interventions. Notable examples include drops in rates of lung cancer and other tobacco-related cancers after reductions in smoking and declines in hepatocellular carcinoma rates among people vaccinated against hepatitis B virus.
“The remaining knowledge gaps on cancer etiology should not be simply ascribed to ‘bad luck’,” says Dr. Wild. “The search for causes must continue while also investing in prevention measures for those cancers where risk factors are known. This is particularly important in the most deprived areas of the world, which face a growing burden of cancer with limited health service resources.”