Circadian genes

Detrimental changes to circadian genes from exposure to LAN present another possible mechanism for the shift work and cancer association.11 The “biological clock” is centered within the hypothalamus in the suprachiasmatic nuclei (SCN), pacemaker neurons that control circadian rhythms in response to repetitive light and dark cycles.14  Proteins encoded by circadian genes (eg, Per1, Per2, Per3, Cry1, Cry2) are in general released on a 24-hour cycle and influence mammalian circadian rhythms through their actions in the SCN.11,16 Through their effects on regulation of cell cycle checkpoints, apoptosis, cell proliferation, and responses to DNA damage, these genes may play a part in tumor suppression that is disrupted by circadian misalignment.11 Mutations in these genes alter circadian cycles; polymorphisms in Per are known to affect individuals’ “morningness/eveningness” proclivity.11,16,17 Cell lines without Per1 and Per2 grow twice as fast as comparable cells with the genes intact. Studies in mice and humans have demonstrated Per1/Per2 suppression of colon cancer cells.1 Deregulated or absent PER1, PER2, and PER3 proteins are highly present in breast and endometrial cancer cells, but not adjacent, normal cells.11


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Sleep deprivation

While nighttime melatonin release is highly regulated by external light, cortisol release, which mediates the wake urge, appears to be driven by endogenous circadian rhythms and is refractory to abrupt changes in sleep/wake cycles.12,18,19  This means it is easier to disrupt the urge to sleep than to disrupt the urge to wake, leaving many shift workers with sleep deficits that have multiple detrimental effects. Sleep deprivation impairs the immune system by shifting the cytokine balance toward type 2 cytokines.11,12  Chronic sleep deprivation alters carbohydrate metabolism and is associated with weight gain, obesity, and type 2 diabetes.20,21  Over a period of 4 years, nurses working night shifts were 5 times as likely to develop metabolic syndrome as those on day shifts.22  Insufficient sleep disrupts normal neuroendocrine axes and related regulatory functions.11,12  However, the role of sleep deprivation per se in increased cancer risk is difficult to isolate. Studies with breast cancer, for example, have produced conflicting data when looking at sleep duration and breast cancer risk.23

Increased Cancer Rate in Shift Workers

A “dose-dependent” association between night shift work and increased breast cancer risk has been supported in multiple studies. In aggregate data from 8 observational studies, women working night shifts had a 40% higher risk for developing breast cancer than similar women not working night shifts.23  In the Nurses Health Study (NHS), night shift work for ≥30 years increased breast cancer risk by 36%; differences were seen between post- and premenopausal women (Table 1).24 

In the NHS II, women who worked rotating night shifts for ≥20 years had a 79% higher breast cancer risk. The trend did not reach significance, perhaps because relatively few women in the study had reached the 20-year mark.25 In a retrospective, case-matched study of newly diagnosed breast cancer, having ever worked the overnight shift increased risk by 60%. In this study, each additional hour per week or year worked at night conveyed additional risk.26 In contrast, a study done by O’Leary and colleagues found an inverse relationship between overnight work and breast cancer risk and only a small increase in risk associated with evening shifts.27 Retrospective and prospective studies suggest an association between higher melatonin levels and lower breast cancer risk, but methodological differences make definitive conclusions difficult.23 The evidence has led some researchers to propose that suppression of melatonin by bright LAN may be considered a breast cancer risk factor.12  The IARC considers shift work, and night shift work in particular, a breast cancer risk factor.11

A few studies have reported increased rates of prostate cancer with shift work. A cohort study of Japanese workers found that the risk for prostate cancer was three time greater (P=0.02) when the workers had rotating shifts rather than fixed night or day shifts.28 Other studies involved long-haul airline workers, and had potential biases.11 These airline studies mostly found a small increased risk associated with shift work, which was higher for long-haul pilots, longer hours of flight time, and older age.11  

In the NHS, women who worked rotating night shifts for ≥15 years had a 35% higher risk for colorectal cancer than those who never worked the night shift (P=0.04); no increase in risk was seen among those with less than 15 years exposure.29  Nurses who worked that shift for ≥20 years had a 47% increased risk of endometrial cancer (P =0.04). The risk was highest when women with a long history of rotating night shifts also were obese.11 No apparent association between shift work and ovarian cancer has emerged in data from the NHS or NHS II.30

Shift Work versus Shift Work Disorder

A subset of shift workers develop shift work disorder (SWD), a circadian rhythm sleep disorder associated with debilitating symptoms of excessive sleepiness and/or insomnia related to shift work. Estimates vary on the percentage of shift workers who meet criteria for SWD, but suggest that anywhere from 14.1% to 53.9% of night- and rotating-shift workers meet the criteria.31-33 Higher rates of gastrointestinal, cardiovascular, and mood disorders are seen with SWD than with shift work itself, but whether SWD also conveys an additional increased risk for cancer is unknown.31,33

What Can be Done?

Short of shutting down overnight shift work, there are few interventions available to workers and employers. Instituting systems to help workers minimize circadian disruption could be useful. Options might include modifying light intensity, using forward-rotating shifts, altering the duration of night shifts either to allow better adaptation (more days) or minimize disruption (fewer days), taking steps to ensure restorative sleep after the shift, or using filter lenses that block melatonin-disrupting blue light.13,34-36 Given the suspected role of linoleic acid in cancer development, night shift workers should be advised to limit nocturnal dietary fat intake, which also might reduce rates of obesity and metabolic disturbance.12  Randomized trials of supplemental melatonin could be designed to determine whether the intervention offsets breast cancer risk for women working shifts.13 Finally, it may be wise to advise women who have breast cancer to avoid night shift work.13 

Conclusion

Epidemiological evidence suggests that exposure to work outside of normal daytime hours increases risk of breast, prostate, colorectal, and endometrial cancers to different degrees and with different levels of confidence.37 The mechanisms underlying this observation are still theoretical, but appear related to circadian disruption due to complex interactions of melatonin secretion, immune dysfunction, sleep deficiency, and metabolic imbalances. Research to improve our understanding of the complex mechanisms and interactions underlying the risk of cancer, and what can be done to counteract them, is needed.