Can shift-work shift epigenetic changes?

描述(由申请人提供)：据推测，现代社会的夜间光线(LAN)可能是工业化国家观察到的乳腺癌风险增加的部分原因，而倒班工作被认为是LAN暴露的最极端形式。2007年10月，国际癌症研究机构(IARC)召集了一个专家小组，通过审查实验室和流行病学研究的证据，评估轮班工作在人类癌症发展中的作用。该专家小组得出结论，“涉及昼夜节律紊乱的轮班工作可能会对人类致癌”(《柳叶刀肿瘤学》，2007)。我们的团队在昼夜节律基因的分子流行病学方面已经完成了开创性的工作，我们已经证明了昼夜节律基因的遗传变异和甲基化变化都使个体容易患乳腺癌。然而，倒班工作是否会导致表观遗传变化仍然是一个悬而未决的问题。考虑到全世界数以百万计的妇女暴露在不合时宜的光线下，特别是通过涉及轮班工作的职业，迫切需要系统地研究轮班工作的生物影响，包括这种暴露的表观遗传后果。在这里，我们建议进行一项人类研究，以检查轮班工作可能导致的全局和特定于基因座的甲基化变化。在拟议的研究中，共有600名女性受试者将从已建立的丹麦预期队列中挑选(300名受试者没有倒班工作历史，300名长期(10年以上)倒班工人)。这些参与者已将可用的血液样本存档，这些样本将用于DNA提取和随后的表观遗传学分析，以确定轮班工作对全球DNA甲基化以及核心昼夜节律基因启动子区甲基化的影响。鉴于IARC最近的结论，以及越来越多的流行病学和生物学证据，这项探索性研究将扩大我们之前的发现，并在更全面地理解时钟与癌症的联系方面开辟新的天地。更重要的是，由于一些表观遗传事件是可以预防的，这项研究的结果将对公众健康产生重大影响，并可能导致乳腺癌预防的新策略。 公共卫生相关性：这项拟议的研究基于未来队列中可用的数据和生物样本，将首次检查长期暴露在夜间(夜班工作)光线下的表观遗传学影响。鉴于国际癌症研究机构最近得出的结论，“涉及昼夜节律紊乱的轮班工作可能会对人类致癌”，加上越来越多的流行病学和生物学证据，这项研究的发现可能为轮班工作在乳腺癌发展中的作用提供可能的生物学机制，并将对指导未来的资源用于适当的初级预防策略具有价值。由于世界范围内职业轮班工作的高流行率，拟议的研究具有广泛的公共健康影响。

DESCRIPTION (provided by applicant): It has been hypothesized that light-at-night (LAN) in modern societies might be partially responsible for the elevated risk of breast cancer observed in industrialized nations, and shift work is regarded as the most extreme form of LAN exposure. In October 2007, the International Agency for Research on Cancer (IARC) assembled an expert panel to assess the role of shift work in human cancer development by reviewing the evidence from laboratory and epidemiological studies. This expert panel concluded that "shift work that involves circadian disruption is probably carcinogenic to humans" (Lancet Oncology, 2007). Our group has completed pioneering work on the molecular epidemiology of circadian genes, and we have demonstrated that both genetic variants and methylation changes in circadian genes predispose individuals to breast cancer. However, whether shift work may contribute to epigenetic changes is still an unanswered question. Considering that millions of women worldwide are being exposed to ill-timed light, particularly through occupations involving shift work, there exists an urgent need to systematically study the biological impact of shift work, including the epigenetic consequences of this exposure. Here, we propose a human study to examine both global and locus-specific methylation changes that may result from shift work. In the proposed study, a total of 600 female subjects will be selected from an established Danish prospective cohort (300 subjects with no history of shift work and 300 long-term (10+ years) shift workers). These participants have archived blood samples available, which will be used for DNA extraction and subsequent epigenetic analysis, in order to determine the impact of shift work on global DNA methylation, as well as methylation in the promoter regions of the core circadian genes. In light of the recent IARC conclusion, along with an increasing body of epidemiological and biological evidence, this exploratory study will extend our previous discoveries and break new ground toward a more comprehensive understanding of the clock-cancer connection. More importantly, because of the preventable nature of some epigenetic events, the results obtained from this study will have considerable public health implications and could lead to new strategies for breast cancer prevention. PUBLIC HEALTH RELEVANCE: This proposed study, based on data and biosamples available from a prospective cohort, will be the first to examine the epigenetic impact of long-term exposure to light at night (night shift work). In light of the recent IARC conclusion that "shift work that involves circadian disruption is probably carcinogenic to humans", along with an increasing body of both epidemiological and biological evidence, the findings from this study may provide possible biological mechanisms for the role of shift work in breast cancer development, and will be valuable in directing future resources to appropriate strategies for primary prevention. Due to the high prevalence of exposure to occupational shift work worldwide, the proposed study has the potential for broad public health implications.