Night-shift Work and Risk of Prostate Cancer

Results From a Canadian Case-Control Study, the Prostate Cancer and Environment Study

Christine Barul; Hugues Richard; Marie-Elise Parent

Disclosures

Am J Epidemiol. 2019;188(10):1801-1811. 

In This Article

Discussion

In this large population-based case-control study, we investigated associations between night-shift work, early-morning shifts, and prostate cancer risk. Our results were generally consistent with the absence of associations with prostate cancer overall, as well as associations stratified by disease aggressiveness. The only suggestive positive associations, albeit weak, were for night-shift schedules with forward rotation and for a high rate of rotation (based on small numbers), especially for low-grade tumors.

The possible mechanisms linking night-shift work and cancer have been reviewed.[5,18] These could explain associations with breast cancer in particular, for which the evidence is most consistent,[19] or with cancers at other sites, including the prostate gland, another hormone-dependent organ. There is substantial evidence from animal and experimental studies that exposure to light at night triggers circadian rhythm dysfunction by suppressing melatonin levels and altering expression of clock genes. Both are key protectors against tumor development through inhibition of tumor growth and maintenance of tissue homeostasis. Multiple biological pathways in the carcinogenicity process, such as DNA repair, cell proliferation, and apoptosis, might be involved. There is a line of evidence for a potential link between circadian disruption and prostate cancer risk more specifically.[20]

Research evaluating this relationship in humans has been limited. In a 2015 meta-analysis based on 5 cohort studies and 3 case-control studies, Rao et al.[21] reported an overall meta–relative risk of 1.24 in night workers, but differences in definitions of night-shift work and the large heterogeneity across studies weakened this finding. Since then, 4 investigations (2 cohort studies and 2 case-control studies) have found positive associations,[22–25] while 2 cohort studies have not.[26,27]

The lack of a consistent definition of night-shift work involving circadian disruption across studies has hampered the ability to draw conclusions from the overall evidence. To our knowledge, ours is the only case-control study to have applied IARC's definition of night-shift work (i.e., work for at least 3 hours between midnight and 5:00 AM). In one cohort study, Hammer et al.[22] also did, reporting no evidence of higher risks among rotating shift workers exposed to night shifts. In another cohort study,[23] night-shift work was defined as a shift that included work between midnight and 5:00 AM, although it was not explicit in the report that at least 3 hours of work had to occur within this period.

Most of the cohort studies investigating the association between night-shift work and prostate cancer risk have reported null findings for ever exposure[26–31] or for duration of night-shift work,[27] in line with our results. In only 1 German prospective cohort study did researchers report elevated risks among participants with the longest duration of night-shift work, with an indication of a dose-response relationship.[23] In the 5 case-control studies conducted to date,[24,25,32–34] results have been mixed. Some found elevated odds ratios, sometimes marginally elevated, for ever exposure,[24,32–34] and most also did for selected metrics. Our findings are consistent with the absence of a clear association with overall prostate cancer, notwithstanding the metric used, including total duration, intensity, and cumulative exposure to night-shift work. These results concur with those from other studies based on the duration of night-shift work[25,32] and/or cumulative exposure.[25,34] However, they contrast with previous observations among workers with the longest durations of night-shift work (odds ratios of 1.38 and 2.68 based on ≥28 years and ≥10 years, respectively)[33,34] and results obtained when long duration was combined with a longer shift length (OR = 2.49) or a higher number of consecutive nights worked (OR = 1.71).[25]

We observed no excess risk among men performing night-shift work in rotation with another shift. While 2 prospective cohort studies found higher risks among rotating shift workers,[22,28] most studies did not replicate this finding.[25,30,31,34] There was weak evidence in our data of elevated risks among night-shift workers with forward rotation schedules and those with the highest rate of shift rotation. Studies evaluating these metrics reported negative findings.[22,25] Forward rotating shifts reportedly have a lesser circadian impact than backward ones.[7]

To date, only 2 studies have examined whether early-morning shifts (based on different definitions) are associated with prostate cancer,[25,33] with divergent results. In our study, employment in early-morning shifts, defined as starting work between 2:00 AM and 6:00 AM, was not associated with prostate cancer risk. We did not include workers who started work between midnight and 2:00 AM in our definition, so early-morning workers and night-shift workers were mutually exclusive in our study. However, had we expanded our definition to include subjects starting work at midnight instead of 2:00 AM, this would have added only 11 controls and 7 cases to our exposed group.

Different patterns of risk have been observed between less aggressive and more aggressive prostate tumors with factors such as alcohol[35] or obesity,[36] suggesting that different types of tumors may have different sets of risk factors and etiology. In support of this, low-grade and high-grade cancer foci progress largely in parallel, diverging early from a common progenitor. Moreover, there appears to be no direct progression from low-grade disease to metastatic disease.[37] We evaluated the possibility that night-shift work and early-morning shift work would be related to risk differently according to disease aggressiveness. This did not appear to be the case. For all exposure metrics, formal statistical testing revealed no heterogeneity in odds ratios between low- and high-grade cancers. Three previous studies have presented odds ratios separately by aggressiveness, although none reported on heterogeneity testing.[22,25,34] In two of them, most positive findings observed for prostate cancer overall were also found for aggressive tumors.[25,34] While our analyses were based on a relatively large number of aggressive cases, the numbers of exposed subjects in the different metric categories were sometimes limited, possibly reducing the ability to detect associations.

Our study had some limitations. Misclassification of night-shift work and early-morning shifts inevitably occurred, which might have brought risk estimates towards the null. However, several factors likely mitigated this to some extent. PROtEuS was specifically conceived to test hypotheses around workplace exposures and prostate cancer. Subjects provided detailed descriptions of each job held, including specific tasks, which may have helped situate them in their context and may have improved reporting. Interviews were conducted face-to-face by interviewers specially trained for occupational studies. Work schedules were coded by industrial hygienists using full job descriptions.

Assessment of specific work metrics at the population level for over 15,000 jobs proved to be quite challenging, in light of changes in schedules within jobs, irregular schedules (such as on-call and emergency work), and complex schedule information, even using the detailed job descriptions industrial hygienists had access to. Unlike studies conducted in homogeneous occupational groups (e.g., nurses), which are typically characterized by fewer types of schedules, the variability in work hours encountered here across a wide range of occupations complicated the exposure assessment considerably. This was particularly the case when assessing the direction and rate of shift rotation, for which confidence in the assessment was lower than for other metrics. Nevertheless, reports of work histories have been shown to be valid,[38] and in a recent validity study in which self-reported exposure to night-shift work was investigated, self-reports of night-shift work showed the best performance compared with other factors.[39]

Another limitation was our lack of information on sleep patterns, rest periods after night-shift work, light-at-night exposure during sleep and during leisure time, and chronotype. A few studies have incorporated information about the latter,[23,25,26,34] but its role has yet to be fully explored.[40] Participation rates were good in our study population, albeit lower among controls. No information on exposure to night-shift work and early-morning shifts was available for nonparticipants. However, according to census data based on area of residence, participants and nonparticipants were found to be very similar in terms of the proportions of recent immigrants, unemployment, educational level, and household income among both cases and controls, which reduces concerns about possible selection bias. The proportions of workers involved in night-shift work and early-morning shifts represented about 22% and 7% of our study population, respectively, which were slightly lower than those in other population-based case-control studies (e.g., 31%–36%[25,34] and 11%,[25] respectively). However, these proportions are expected to vary across studies, as they reflect different regional industrial activities, age distributions, and definitions of night-shift work and early-morning shifts.

Detailed job descriptions enabling assessment of night-shift work and early-morning shifts were collected only for jobs lasting 2 years or more, in order to decrease interview burden, since some subjects reported up to 12 jobs. However, jobs lasting under 2 years represented less than 4% of overall work years, on average.[41] Imputation was applied to a low percentage of jobs, and results were similar to those from complete-case analyses.

Epigenetic studies on prostate cancer have found positive associations between some polymorphisms of genes involved in circadian rhythm[42–49] or the aggregate variation in circadian genes[48] and prostate cancer. We could not evaluate this aspect of the relationship in our study.

Several study strengths reinforce the robustness of our findings. The present study is one of a very few, and the largest based on the number of cases (to our knowledge), to have applied an exact definition of night-shift work involving circadian disruption based on work hours following IARC's recommendation.[7] We were able to investigate night-shift work through several dimensions. The possibility of residual confounding cannot be totally excluded, although very few risk factors for this cancer, including occupational risk factors, have been clearly established.[50] The wide range of occupations covered here may reduce the likelihood of strong confounding by a commonly shared factor, occupational or other, as compared with that in a specific occupation or industry. Finally, information on screening enabled us to evaluate the role of undiagnosed prostate cancers among controls in our findings.

In conclusion, results from this study lend no support for a major role of night-shift work or early-morning shifts in prostate cancer development.

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