Can shift-work shift epigenetic changes?

描述（由申请人提供）：据推测，现代社会中的夜间照明（LAN）可能是工业化国家中观察到的乳腺癌风险升高的部分原因，轮班工作被认为是LAN暴露的最极端形式。2007年10月，国际癌症研究机构（癌症研究机构）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，“涉及昼夜节律破坏的轮班工作可能对人类致癌”（Lancet Oncology，2007）。我们的团队已经完成了关于昼夜节律基因的分子流行病学的开创性工作，我们已经证明了昼夜节律基因中的遗传变异和甲基化变化使个体易患乳腺癌。然而，轮班工作是否可能有助于表观遗传变化仍然是一个悬而未决的问题。考虑到全世界数百万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，我们提出了一项人类研究，以检查全球和基因座特异性甲基化的变化，可能会导致轮班工作。在拟定的研究中，将从已建立的丹麦前瞻性队列中共选择600例女性受试者（300例无轮班史的受试者和300例长期（10年以上）轮班工人）。这些参与者已经存档了可用的血液样本，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甲基化的影响，以及核心昼夜节律基因启动子区域的甲基化。鉴于最近IARC的结论，沿着越来越多的流行病学和生物学证据，这项探索性研究将扩展我们以前的发现，并为更全面地了解时钟-癌症联系开辟新的天地。更重要的是，由于一些表观遗传事件的可预防性，本研究获得的结果将具有相当大的公共卫生意义，并可能导致乳腺癌预防的新策略。 公共卫生相关性：这项基于前瞻性队列的数据和生物样本的拟议研究将是第一个研究夜间长期暴露于光线（夜班工作）的表观遗传影响的研究。鉴于最近的IARC的结论，“轮班工作，涉及昼夜节律的破坏可能是致癌的人类”，沿着越来越多的机构的流行病学和生物学证据，这项研究的结果可能提供可能的生物学机制轮班工作在乳腺癌的发展中的作用，并将是有价值的指导未来的资源，以适当的战略，初级预防。由于全球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卫生影响的潜力。

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.