Yong Zhu, PhD, assistant professor in the Department of Epidemiology and Public Health at Yale University School of Medicine, has been investigating circadian rhythms and cancer risk. In a recent article in the journal Medical Hypotheses, he proposed a provocative idea: that non-Hodgkin’s lymphoma could be linked to disruptions of circadian rhythm. PDQhealth asked him to explain.

Q. Why is non-Hodgkin’s lymphoma of special interest to epidemiologists?

Unlike many types of cancer, non-Hodgkin’s lymphoma is on the rise, and we don’t know why. Many cancers have identifiable risk factors. But with NHL, we really don’t understand what causes the disease. Some viruses have been linked to NHL. Exposure to certain toxic chemicals has also shown a weak association. But the only recognized risk factor is abnormal regulation of the immune system. I’m interested in a possible link between circadian rhythm disruptions and cancer, so it makes sense to look at NHL to see if that might explain the disease and why the incidence is rising.

Q. What are circadian rhythm disruptions?

Almost all life on earth has adapted to alternating light and darkness, night and day. This circadian rhythm turns out to have an impact on almost every single biological pathway. Research has now identified genes that regulate circadian clocks within cells. So far, 9 human circadian genes have been identified. In the modern industrialized world, with electric light, we’re able to disrupt natural circadian rhythms–by staying up late at night and sleeping in the morning, for example. Shift work and traveling to distant time zones also disrupt circadian rhythm. The hypothesis is that these disruptions may affect cell functions and promote certain forms of cancer.

Q. What’s the evidence so far?

Several epidemiological studies have shown an association between shift work and higher risk of certain cancers, such as hormone-related breast and prostate cancer. Pilots, flight attendants, and nurses appear to be at higher risk. Our work is molecular epidemiology, which looks at genetic patterns and their association with disease risk. We’ve provided the first evidence linking a certain pattern of circadian genes to risk of NHL and breast cancer. More recently, we looked at prostate cancer. Again, we found a link between circadian gene patterns and risk of the disease.

Q. How strong is the evidence for non-Hodgkin’s lymphoma?

The evidence is preliminary because researchers are just beginning to look. A study of men working for Air Canada showed increased risk of a form of leukemia, which is a cancer of blood cells, like lymphoma. Studies have also shown that immune cells, including the cells that become cancerous in lymphoma, called B cells, follow circadian rhythms. Disruptions of those rhythms could cause cells to dysfunction. We still need to understand the mechanism. The circadian genes I mentioned are transcriptional factors. That means they don’t code for enzymes themselves but rather turn on or off other genes, which directly affect a wide range of biological processes. So disruptions in circadian rhythm could affect many functions, including cell growth. And of course cancer occurs when cells grow out of control. Interestingly, there’s evidence that inherited differences in circadian genes can even affect behavior. It’s well known that some people are morning people and others are evening people—night owls and morning larks, they’re sometimes called. That behavioral difference has been linked to a mutation in one circadian gene.

Q. What are the implications for cancer prevention?

One hope is that we will identify specific circadian gene patterns associated with an increased non-Hodgkin’s lymphoma cancer risk that could serve as a marker for the disease. Eventually we may be able to use genetic tests to identify people who are at special risk from circadian disruptions and others who can adapt to shift work and circadian disruptions with little trouble. If shift work really is hazardous to health, as a society we should try to limit it as much as possible. About 15–20% of the working population in Europe and the US is engaged in shift-work that involves nightwork. We’re also looking to see if circadian gene patterns affect a person’s response to treatment. If the molecule a drug targets is typically expressed on cells in the morning, for example, then that drug will be more effective if it’s given in the morning than at night. It’s important to remember that the link between circadian rhythm disruption and non-Hodgkin’s lymphoma is still a hypothesis. We have a lot of work to do to show if it really exists.

Q. In the mean time, should we all keep more regular hours?

That’s certainly what our work suggests. Circadian rhythm is so fundamental to biological processes that disrupting it seems to have many consequences. The invention of electric lighting and the rise of shift work could explain increases in cancer rates in many modern industrialized countries over the past century. Those changes could have a tremendous public health impact that we’re only just beginning to understand.

Tags: circadian rhythms, NHL, non-Hodgkin's lymphoma