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Scientists respond to study on cancer risk factors

The following response was provided by Drs. Cristian Tomasetti and Bert Vogelstein in regards to a new paper published in the journal Nature:

Scientific debate on the factors responsible for cancer is a welcome and important part of solving the challenges we face in reducing the burden of this disease . The differences between our conclusions and those of Hannun et al. are dramatic. Through re-evaluation of our data, the authors conclude that virtually all forms of cancer are the result of extrinsic factors (Fig. 3 of Hannun et al.). Their analysis therefore supports the widely held belief that nearly all cancers of all types are preventable.

In contrast, we concluded that some cancers are largely the result of environmental factors — such as those associated with exposure to cigarette smoke or sunlight, or obesity — while other cancer types are largely unavoidable. Moreover, we concluded that all cancers, of all types, are likely to be caused by a mixture of the mutations induced by external influences — avoidable in principle — and those caused by the replication of normal stem cells — unavoidable and just bad luck. Our conclusions were based on our discovery of the extraordinarily tight relationship between stem cell divisions in normal tissue and the incidence of cancer in that tissue. The striking contrast between our conclusions and those of Hannun et al. has important implications about the information that should be provided to cancer patients and the public.

We were surprised that Hannun et al. attempted to determine the proportion of individual cancers due to extrinsic factors from our stem cell data, because that is impossible to do in a reliable and mathematically sound fashion. This explains why some of the authors’ estimates of the contributions of extrinsic factors to cancer are incongruent with the voluminous epidemiologic research on these cancers. For example, Hannun et al. concluded that more than 99 percent of prostate cancers, more than 98 percent of thyroid cancers, more than 95 percent of brain cancers and more than 94 percent of testicular cancers are caused by environment factors (Fig. 3 of Hannun et al.), while epidemiologists have concluded that zero or less than 1 percent of any of these cancer types can be ascribed to extrinsic factors (

In contrast, we believe that the estimates made by decades of painstaking work by epidemiologists are accurate, i.e., that between 21 to 42 percent of cancers in the U.S. are preventable. We attempted to identify the risk factors that might have contributed to the remaining cancers. We discovered strong evidence supporting the idea that replicative mutations, made during normal stem cell divisions, are a major risk factor. Our analyses further indicated that certain cancers, such as those of the lung and skin, had a much larger non-replicative component than other cancers, such as those of the brain, bone or pancreas.

Our study was the first to provide scientific evidence to support the idea that we can now confidently tell most parents of children with cancers, as well as adult patients with certain types of cancer, that there was nothing they could have done to avoid their plight. By perpetuating the myth that virtually all cancers are due to extrinsic factors, we can inadvertently add guilt to already tragic situations. At the same time, our study confirmed the well-known importance of avoiding the known risk factors for cancer, such as cigarette smoke, sunlight and obesity.

Cristian Tomasetti
Bert Vogelstein