Clock-cancer connection in non-Hodgkin’s lymphoma

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Summary

The universal 24-hour circadian clock has a profound impact on many daily biological processes. Disturbance of circadian rhythms has been implicated in the etiologies of many chronic illnesses, including cancer; with correlations most profoundly found among hormone-related breast and prostate cancers. Given the fact that circadian disruption can cause immune deregulation, which is so far the only established risk factor for non-Hodgkin’s lymphoma (NHL), we hypothesize that altered circadian rhythms due to environmental factors and/or genetic variations in genes responsible for maintaining circadian rhythms may result in the deregulation of clock-associated biological processes such as immune responses and activities, and consequently influence an individual’s risk of developing NHL. Our recent findings provided the first molecular epidemiological evidence linking a major circadian gene to NHL and warrant further investigation. Confirmation of this hypothesis will further add to our understanding of the role of the circadian clock in lymphomagenesis and facilitate the development of novel risk and prognostic biomarkers for NHL.

Introduction

Currently, non-Hodgkin’s lymphomas (NHL) is among the most rapidly increasing malignancies, increasing to a point where it accounted for 4% of all new cancer cases in 2005 in the United States [1]. Despite tremendous efforts to improve our understanding of this cancer, its etiology remains largely unknown with the only well-established risk factor for NHL being immune deregulation [2]. Given that several essential components of the innate immune system are influenced by the 24-hour circadian rhythm [3], [4], [5], we speculate that circadian disruption might play a role in lymphomagenesis by detrimentally affecting immune activity. Furthermore, we hypothesize that genetic variations in genes responsible for maintaining circadian rhythm might act as a novel panel of biomarkers associated with an individual’s susceptibility to NHL.

Section snippets

Clock-cancer connection: epidemiological evidence

The vast majority of organisms experience a 24-hour oscillation of many essential biochemical, physiological and behavioral processes. This oscillation arises from an ancient adaptation to the rotation of the earth and is one of the fundamental components of our biological world. Disruptions of this critical rhythm have the potential to significantly affect our health, and may play a significant role in tumor development [6].

A connection between cancer development and the circadian cycle has

Clock-cancer connection: genetic evidence

To date, there have been nine core circadian genes identified: Clock, casein kinase Iε (CKIε), cryptochrome 1(Cry1), cryptochrome 2 (Cry2), Period1 (Per1), Period2 (Per2), Period3 (Per3), Bmal1, and NPAS2. A model of transcription–translation feedback loops of these circadian genes has been proposed to explain the molecular clockwork [17] in which cell functions are regulated through the expression of clock-controlled genes. It has been estimated that 2–10% of all mammalian genes are

Possible mechanisms: clock-controlled immune function

Circadian rhythms have been observed in immune activities, including in natural killer (NK) cells, which are an essential component of the innate immune system that responds to infections and cancerous growth [3]. The expression of NK cells oscillates throughout a 24 h period, with peak expression occurring in the early morning [4]. Numerous other components of the immune system, such as T-helper, T-suppressor and splenic B-cells, also display a 24-hour oscillation similar to that of the NK

Hypothesis

Given the established association between immune deregulation and non-Hodgkin’s lymphoma (NHL), we speculate that circadian rhythm might play a role in lymphomagenesis by affecting immune activity. For example, increased exposure to light at night will disrupt circadian rhythms and consequently elevate the risk of NHL. Furthermore, genetic and epigenetic variations in circadian genes may result in deregulation of circadian rhythms and other biological processes regulated by these genes. We

Testing the hypothesis

From an epidemiological perspective, a well-designed population-based case-control study would provide evidence for the role of circadian disruption in NHL. In this type of study, the questionnaire for assessing environmental light exposures and sleeping patterns must be carefully designed in order to ensure meaningful results. Additional studies involving nocturnal occupational groups, such as shift workers (e.g. nurses), would also test this hypothesis in NHL.

Genetic and epigenetic analyses

Conclusions

We propose that some NHL cases could be explained by light-induced circadian disruptions and/or genetic/epigenetic variations in circadian genes and/or gene-environment interactions between these two factors. We also propose that the clock-regulated immune activities might be one potential mechanism involved in lymphomagenesis. These hypotheses are testable in a molecular epidemiological study and could lead to the development of novel circadian risk and prognostic biomarkers for NHL.

Acknowledgements

We thank Derek Leaderer for editorial assistance. This work was supported by the US National Institutes of Health (Grants CA122676, CA110937, and CA108369).

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