Extrinsic factors cause the majority of cancers, not ‘bad luck’

Global media coverage of research by our group at Stony Brook University, recently published in Nature, underscores public interest in the causes and risk factors of cancer. A year ago, a different study had advanced the concept that "bad luck" could be the driver of most cancer and that primary prevention measures may not be effective.

That was a bold assertion with major implications, because it suggested that the general public should not worry about trying to prevent cancer. In our research in Nature, we used several alternative analyses and mathematical modeling to illustrate that most cancers are not the result of "bad luck," but that a majority of cancers appear to be driven more by external factors.

The fundamental question we tackled is the extent to which cancer is caused by either "intrinsic" factors – essentially the random cell mutations that can occur when cells, with the potential of initiating cancer, divide – or by "extrinsic" or external factors that may be preventable, such as smoking, diet and exposure to certain viruses or toxins.

This finding has crucial implications. It underscores the importance of conducting research into identifying external risk factors that lead to cancer and of investment in research that can lead to prevention. It also makes clear that early prevention – not just late (secondary or tertiary) prevention and treatment – is vital.

The distinction – in the case of skin cancer, for instance – is that in primary prevention everyone is encouraged to restrict unprotected exposure to the sun; in later prevention, only those who develop skin cancer or are at a particularly high risk for it would be advised to avoid unprotected exposure. If most cancers are caused by bad luck, then only secondary prevention would be necessary. Our results strongly argue against that.

In the earlier research that had suggested that "bad luck" is a major factor for causing many cancers, the investigators had analyzed data on risks for 31 different types of cancer. They examined the total number of times stem cells divide in the course of a lifetime, and they correlated that to the lifetime risks of developing cancer. They then concluded that about 67 percent of cancers are attributable to intrinsic factors. Many cancer researchers contested the claims, but none attempted a rigorous and analytical evaluation aimed at differentiating the effects of intrinsic vs extrinsic factors.

Our Stony Brook team used four approaches to reach our conclusion. First, and in a biologically-driven analysis based on that earlier study and using the same data, we assumed that if cancer is caused primarily by intrinsic factors, then tissues that have similar numbers of stem cell divisions—like the lung and pancreatic islet—should have similar cancer rates. Yet lung cancer occurs at a much higher rate than pancreatic islet cancer. How can that be if "bad luck" based on the number of cell divisions is the primary driver? This allowed us to define a group of cancers where intrinsic risk appears to play a key role, revealing that the majority of cancers were more likely to be susceptible to external factors.

Next, we evaluated epidemiologic evidence. We studied data from the Surveillance, Epidemiology and End Results Program, which showed substantially increasing U.S. rates in certain cancer types from 1973-2012. That suggests that these cancers are affected primarily by external factors, as the way cells divide does not change over such a short time in history. This was supported by significant epidemiological evidence in the literature showing that many cancers such as breast cancer and prostate cancer are more prevalent in certain parts of the world. Even immigrants who move from countries with low cancer rates soon acquire the higher risk of their new country.

Third, we evaluated recent studies on cancer genetics whereby specific mutational signatures were defined in cancer, the "fingerprints" left on genomes during mutation. This analysis revealed that many cancers, such as colorectal cancer, melanoma, cervical cancer, and liver cancer, show large percentages of extrinsic signatures.

Finally, we conducted computational analyses to model the lifetime cancer risk that would arise from mutations occurring based on the number of mutations required to cause a cancer. The analysis revealed that when three or more mutations are required for cancer onset (which is a currently accepted parameter), intrinsic factors are far from sufficient to account for the observed risks, indicating small percentages of intrinsic cancer risks in many cancers.

Most importantly, all of these analyses independently identified the same contribution of extrinsic factors (approximately 70-90 percent) to cancer risk, and they all pointed to the same cancers as being the most susceptible to extrinsic factors.

It is vital that the public understand the primary message of this research: much of cancer is potentially preventable. Therefore, the public should take action – refraining from smoking, eating healthily, using sunscreen – to lessen their cancer risk. Government agencies and private research funders should also prioritize prevention. A continued multifaceted approach to beating all forms of cancer is crucial, but avoiding cancer in the first place is better than treating it.

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