Richard G. Stevens

Body Iron Stores and the Risk of Cancer

Because of evidence that increased body iron stores are associated with an increased risk of cancer, we examined iron status and cancer risk in the first National Health and Nutrition Examination Survey, a survey of more than 14,000 adults begun in 1971, with follow-up between 1981 and 1984. Among 242 men in whom cancer developed, the mean total iron-binding capacity was significantly lower (61.4 vs. 62.9 mumol per liter; P = 0.01) and transferrin saturation was significantly higher (33.1 vs. 30.7 percent; P = 0.002) than among 3113 men who remained free of cancer. The risk of cancer in men in each quartile of transferrin-saturation level relative to the lowest quartile was 1.00, 1.01, 1.10, and 1.37 (P = 0.02 for trend). The serum albumin level was significantly lower in men in whom cancer developed than in those who remained cancer-free. Among women, those in whom cancer developed did not have significantly lower total iron-binding capacity or higher transferrin saturation than those who remained cancer-free. However, a post hoc examination of 5367 women (203 with cancer) yielded a relative risk of 1.3 (95 percent confidence interval, 0.9 to 1.9) associated with a very high transferrin saturation (greater than or equal to 36.8 percent, a value in the highest quartile among men); in 5228 women with at least six years of follow-up (149 with cancer), the relative risk associated with transferrin saturation above this level was 1.5 (1.0 to 2.2). These results are consistent with the hypothesis that high body iron stores increase the risk of cancer in men. The possibility that a similar association exists in women requires further study.

Meeting Report: The Role of Environmental Lighting and Circadian Disruption in Cancer and Other Diseases

Light, including artificial light, has a range of effects on human physiology and behavior and can therefore alter human physiology when inappropriately timed. One example of potential light-induced disruption is the effect of light on circadian organization, including the production of several hormone rhythms. Changes in light–dark exposure (e.g., by nonday occupation or transmeridian travel) shift the timing of the circadian system such that internal rhythms can become desynchronized from both the external environment and internally with each other, impairing our ability to sleep and wake at the appropriate times and compromising physiologic and metabolic processes. Light can also have direct acute effects on neuroendocrine systems, for example, in suppressing melatonin synthesis or elevating cortisol production that may have untoward long-term consequences. For these reasons, the National Institute of Environmental Health Sciences convened a workshop of a diverse group of scientists to consider how best to conduct research on possible connections between lighting and health. According to the participants in the workshop, there are three broad areas of research effort that need to be addressed. First are the basic biophysical and molecular genetic mechanisms for phototransduction for circadian, neuroendocrine, and neurobehavioral regulation. Second are the possible physiologic consequences of disrupting these circadian regulatory processes such as on hormone production, particularly melatonin, and normal and neoplastic tissue growth dynamics. Third are effects of light-induced physiologic disruption on disease occurrence and prognosis, and how prevention and treatment could be improved by application of this knowledge.

Circadian Disruption and Breast Cancer: From Melatonin to Clock Genes

The global impact of breast cancer is large and growing. It seems clear that something about modern life is the culprit, yet there is thus far a lack of satisfactory explanations for most of the increases in risk as societies industrialize. Support has developed for a possible role of “circadian disruption,” particularly from an altered-lighted environment (such as light at night). Lighting during the night of sufficient intensity can disrupt circadian rhythms, including reduction of circulating melatonin levels and resetting of the circadian pacemaker of the suprachiasmatic nuclei. Reduced melatonin may increase breast cancer risk through several mechanisms, including increased estrogen production and altered estrogen receptor function. The genes that drive the circadian rhythm are emerging as central players in gene regulation throughout the organism, particularly for cell-cycle regulatory genes and the genes of apoptosis. Aspects of modern life that can disrupt circadian rhythms during the key developmental periods (eg, in utero and during adolescence) may be particularly harmful. Epidemiologic studies should consider gene and environment interactions such as circadian gene variants and shift work requirements on the job.

Circulating sex hormones and breast cancer risk factors in postmenopausal women: reanalysis of 13 studies.

Background:Breast cancer risk for postmenopausal women is positively associated with circulating concentrations of oestrogens and androgens, but the determinants of these hormones are not well understood.Methods:Cross-sectional analyses of breast cancer risk factors and circulating hormone concentrations in more than 6000 postmenopausal women controls in 13 prospective studies.Results:Concentrations of all hormones were lower in older than younger women, with the largest difference for dehydroepiandrosterone sulphate (DHEAS), whereas sex hormone-binding globulin (SHBG) was higher in the older women. Androgens were lower in women with bilateral ovariectomy than in naturally postmenopausal women, with the largest difference for free testosterone. All hormones were higher in obese than lean women, with the largest difference for free oestradiol, whereas SHBG was lower in obese women. Smokers of 15+ cigarettes per day had higher levels of all hormones than non-smokers, with the largest difference for testosterone. Drinkers of 20+ g alcohol per day had higher levels of all hormones, but lower SHBG, than non-drinkers, with the largest difference for DHEAS. Hormone concentrations were not strongly related to age at menarche, parity, age at first full-term pregnancy or family history of breast cancer.Conclusion:Sex hormone concentrations were strongly associated with several established or suspected risk factors for breast cancer, and may mediate the effects of these factors on breast cancer risk.

Light-at-night, circadian disruption and breast cancer: assessment of existing evidence

BACKGROUND Breast cancer incidence is increasing globally for largely unknown reasons. The possibility that a portion of the breast cancer burden might be explained by the introduction and increasing use of electricity to light the night was suggested >20 years ago. METHODS The theory is based on nocturnal light-induced disruption of circadian rhythms, notably reduction of melatonin synthesis. It has formed the basis for a series of predictions including that non-day shift work would increase risk, blind women would be at lower risk, long sleep duration would lower risk and community nighttime light level would co-distribute with breast cancer incidence on the population level. RESULTS Accumulation of epidemiological evidence has accelerated in recent years, reflected in an International Agency for Research on Cancer (IARC) classification of shift work as a probable human carcinogen (2A). There is also a strong rodent model in support of the light-at-night (LAN) idea. CONCLUSION If a consensus eventually emerges that LAN does increase risk, then the mechanisms for the effect are important to elucidate for intervention and mitigation. The basic understanding of phototransduction for the circadian system, and of the molecular genetics of circadian rhythm generation are both advancing rapidly, and will provide for the development of lighting technologies at home and at work that minimize circadian disruption, while maintaining visual efficiency and aesthetics. In the interim, there are strategies now available to reduce the potential for circadian disruption, which include extending the daily dark period, appreciate nocturnal awakening in the dark, using dim red light for nighttime necessities, and unless recommended by a physician, not taking melatonin tablets.

Considerations of circadian impact for defining 'shift work' in cancer studies : IARC Working Group Report.

Based on the idea that electric light at night might account for a portion of the high and rising risk of breast cancer worldwide, it was predicted long ago that women working a non-day shift would be at higher risk compared with day-working women. This hypothesis has been extended more recently to prostate cancer. On the basis of limited human evidence and sufficient evidence in experimental animals, in 2007 the International Agency for Research on Cancer (IARC) classified ‘shift work that involves circadian disruption’ as a probable human carcinogen, group 2A. A limitation of the epidemiological studies carried out to date is in the definition of ‘shift work.’ IARC convened a workshop in April 2009 to consider how ‘shift work’ should be assessed and what domains of occupational history need to be quantified for more valid studies of shift work and cancer in the future. The working group identified several major domains of non-day shifts and shift schedules that should be captured in future studies: (1) shift system (start time of shift, number of hours per day, rotating or permanent, speed and direction of a rotating system, regular or irregular); (2) years on a particular non-day shift schedule (and cumulative exposure to the shift system over the subjects working life); and (3) shift intensity (time off between successive work days on the shift schedule). The group also recognised that for further domains to be identified, more research needs to be conducted on the impact of various shift schedules and routines on physiological and circadian rhythms of workers in real-world environments.

Electric power, pineal function, and the risk of breast cancer

Breast cancer is the leading cause of cancer death in women in the industrialized world, and the rates of breast cancer incidence are rising. Although risk is high in industrialized societies, it is low in nonindustrialized areas. The search for the causes of breast cancer has not yet yielded a convincing explanation for the geographic and temporal patterns in the occurrence of breast cancer. Generation of electric power is a hallmark of industrialization, and two products of electric power, light‐at‐night (LAN) and electromagnetic fields (EMF), may affect breast cancer risk. Exposure to either LAN or EMF can decrease production of melatonin by the pineal gland. Melatonin, in turn, has been shown to suppress mammary tumorigenesis in experimental animals. Moreover, recent epidemiological findings indicate an increased risk of breast cancer in workers occupationally exposed to EMF. On the basis of these considerations, it is proposed that the use of electrical power accounts, in part, for the higher risks of breast cancer in industrialized societies.—Stevens, R. G.; Davis, S.; Thomas, D. B.; Anderson, L. E.; Wilson, B. W. Electric power, pineal function, and the risk of breast cancer. FASEB J. 6: 853‐860; 1992.

Sleep Duration and Breast Cancer: A Prospective Cohort Study

Breast cancer incidence has increased during recent decades for reasons that are only partly understood. Prevalence of sleeping difficulties and sleepiness has increased, whereas sleeping duration per night has decreased. We hypothesized that there is an inverse association between sleep duration and breast cancer risk, possibly due to greater overall melatonin production in longer sleepers. This population-based study includes information from women born in Finland before 1958. Sleep duration, other sleep variables, and breast cancer risk factors were assessed by self-administered questionnaires given in 1975 and in 1981. Breast cancer incidence data for 1976 to 1996 was obtained from the Finnish Cancer Registry. Hazard ratios (HR) and 95% confidence intervals (CI) were obtained from Cox proportional hazards models adjusting for potential confounders. Altogether, 242 cases of breast cancer occurred over the study period among the 12,222 women with sleep duration data in 1975. For these women, the HRs for breast cancer in the short (< or =6 hours), average (7-8 hours), and long sleep (> or =9 hours) duration groups were 0.85 (CI, 0.54-1.34), 1.0 (referent), and 0.69 (CI, 0.45-1.06), respectively. Analysis restricted to the 7,396 women (146 cases) whose sleep duration in 1975 and 1981 were in the same duration group (stable sleepers) yielded HRs of 1.10 (CI, 0.59-2.05), 1.0, and 0.28 (CI, 0.09-0.88), with a decreasing trend (P = 0.03). This study provides some support for a decreased risk of breast cancer in long sleepers.

Light at Night Co‐distributes with Incident Breast but not Lung Cancer in the Female Population of Israel

Recent studies of shift‐working women have reported that excessive exposure to light at night (LAN) may be a risk factor for breast cancer. However, no studies have yet attempted to examine the co‐distribution of LAN and breast cancer incidence on a population level with the goal to assess the coherence of these earlier findings with population trends. Coherence is one of Hills “criteria” (actually, viewpoints) for an inference of causality. Nighttime satellite images were used to estimate LAN levels in 147 communities in Israel. Multiple regression analysis was performed to investigate the association between LAN and breast cancer incidence rates and, as a test of the specificity of our method, lung cancer incidence rates in women across localities under the prediction of a link with breast cancer but not lung cancer. After adjusting for several variables available on a population level, such as ethnic makeup, birth rate, population density, and local income level, a strong positive association between LAN intensity and breast cancer rate was revealed (p<0.05), and this association strengthened (p<0.01) when only statistically significant factors were filtered out by stepwise regression analysis. Concurrently, no association was found between LAN intensity and lung cancer rate. These results provide coherence of the previously reported case‐control and cohort studies with the co‐distribution of LAN and breast cancer on a population basis. The analysis yielded an estimated 73% higher breast cancer incidence in the highest LAN exposed communities compared to the lowest LAN exposed communities.

Mutations in BRAF and KRAS Differentially Distinguish Serrated versus Non-Serrated Hyperplastic Aberrant Crypt Foci in Humans

We previously reported that colon carcinomas, adenomas, and hyperplastic polyps exhibiting a serrated histology were very likely to possess BRAF mutations, whereas when these same advanced colonic lesions exhibited non-serrated histology, they were wild type for BRAF; among hyperplastic polyps, KRAS mutations were found mainly in a non-serrated variant. On this basis, we predicted that hyperplastic aberrant crypt foci (ACF), a putative precancerous lesion found in the colon, exhibiting a serrated phenotype would also harbor BRAF mutations and that non-serrated ACF would not. In contrast, KRAS mutations would be found more often in the non-serrated ACF. We examined 55 ACF collected during screening colonoscopy from a total of 28 patients. Following laser capture microdissection, DNA was isolated, and mutations in BRAF and KRAS were determined by direct PCR sequencing. When hyperplastic lesions were further classified into serrated and non-serrated histologies, there was a strong inverse relationship between BRAF and KRAS mutations: a BRAF(V600E) mutation was identified in 10 of 16 serrated compared with 1 of 33 non-serrated lesions (P = 0.001); conversely, KRAS mutations were present in 3 of 16 serrated compared with 14 of 33 non-serrated lesions. Our finding of a strong association between BRAF mutations and serrated histology in hyperplastic ACF supports the idea that these lesions are an early, sentinel, or a potentially initiating step on the serrated pathway to colorectal carcinoma.