The Randomness of Cancer

A major scientific study grabbed headlines recently, and the implications of its findings may affect many of us, if not all of us. In a paper published in Science by Cristian Tomasetti, Lu Li and Bert Vogelstein of Johns Hopkins University, the authors report that nearly two-thirds of known cancer causing mutations can be attributed to random mistakes that occur during DNA replication. In other words, the vast majority of these mutations occur in a spontaneous, uncontrollable way— it may not matter how you live your life, or what measures you take to decrease your chance of developing cancer. As the authors and the press put it, it really just comes down to luck.

gene-mutationDisturbing? For many, yes. It’s not easy to accept that one’s luck in activities such as winning the lottery may also apply to whether or not you will be touched by cancer. That is partly why this study is gaining so much attention.

As the authors explain in their publication, until now most cancer-causing mutations had been attributed to two major sources: inherited and environmental factors. But they found that a third kind of mutation, replicative (R) mutations that arise from unavoidable errors associated with DNA replication, account for 66 percent of mutations that drive cancer.

The study was a follow up of an earlier study by the same researchers when they examined cancer data solely from the United States. This time they embarked on a much more comprehensive and global analysis that included data from 69 different countries and 32 different types of cancer. Using a mathematical modeling approach they compared cancer sequencing and epidemiological data to estimate the fraction of mutations that gave rise to replication, environmental and hereditary factors. Environmental factors, such as smoking, were found to account for 29 percent of mutations whereas hereditary factors accounted for only five percent of mutations.

Interestingly, the study also showed that the percentage of cancer-causing mutations by each of the three different factors varied for different types of cancer. In pancreatic cancer samples for example, DNA replication errors accounted for 77 percent of mutations. Lung cancer mutations on the other hand were predominantly caused by environmental factors (65 percent) compared with DNA copying errors (35 percent).

What are the implications?

As the authors and other oncology experts have been quick to point out, the implications of this pivotal study may reverberate not only on a scientific level, but on a personal level as well.

The importance of early cancer detection is one message the authors are striving to emphasize. Co-author Vogelstein stated in many follow up news articles by major news agencies that the best way to keep up with the increased rate of random mutations as we age is to find better ways to detect cancer in its early stage. The authors write in their conclusion that not enough emphasis is placed on early detection studies. And they continue by stating that while primary prevention is the best way to reduce cancer deaths, secondary prevention through early detection and intervention can also be lifesaving.

Another implication of their study is that the prevalence of random mutations caused by the natural process of cell division means we may have to accept the role of fate, or luck, in any person’s development of cancer. This perspective may offer comfort to the millions of patients who receive the unfair diagnosis of cancer despite living their lives in ways to avoid the probability of the disease. Cancer patients often feel a sense of guilt that they could have done more to fend off cancer and tend to question lifestyle decisions they made prior to diagnosis. But the high rate of R mutations in our population implies that cancer may have occurred no matter what choices they made. This can also help to assuage the “why me?” question many cancer patients ask when facing the shock of a cancer diagnosis.

What about the implications for research scientists working in the area of cancer biology and how might they be affected by the finding of the significant role R mutations play in cancer etiology? These random copy errors occur when cells divide, and they include “typos,” insertions, or deletions of genes, as well as epigenetic changes and gene rearrangements. Perhaps scientists whose work relates to cell division might now re-shift their focus to try and identify the regulators and gatekeepers of DNA replication. Maybe we’ll see renewed effort and increased funding support to hone in on the cellular machinery involved in DNA replication. And that could lead to a better understanding of how to modulate the DNA mutations that inflict damage on genes and spur cancerous growth.

This story will continue to unfold as the surprising findings by Tomasetti et al settle. No doubt other expert geneticists will want an opportunity to weigh in and pursue related studies to substantiate the data. In the meantime, it’s important to keep in mind that while we’re not able to control our inherited or random genetic mutations, we can continue to minimize environmental exposures known to drive cancer.


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