Clock Genes, Night Work, and Breast Cancer Risk

夜间光照可能通过抑制褪黑激素对乳腺癌风险产生不利影响， 一种与昼夜节律密切相关的荷尔蒙，并显示出防癌效果。 观察性研究一直将夜间工作与乳腺癌风险的增加联系在一起。至 到目前为止，已经确定了9个人类昼夜节律紊乱的候选基因，以及常见的突变 其中四人与季节性情感障碍、家族性睡眠晚期综合征有关， 和白天的喜好。在小鼠中，mPer2功能的丧失会导致肿瘤发展和 DMAdamage响应中的缺陷。在人类中，数据虽然仍然稀少，但表明了积极的 某些时钟基因突变与乳腺癌风险之间的关系。因此，未来对 乳腺癌风险和昼夜节律紊乱之间的联系，如夜间工作人员所经历的， 必须考虑时钟基因的作用。在这项研究中，我们建议利用现有的数据 以正在进行的护士健康研究II(NHS II)为样本进行嵌套病例对照研究 评估生物钟候选基因中常见变异与乳腺癌的关系 风险，以及与夜班工作的互动。我们将评估护士患乳腺癌的风险是多少 受时钟基因不同多态的影响，并将表征这些关联中的差异 根据护士的夜班情况。进一步研究分子节律性与分子生物学之间的关系 昼夜节律系统的其他标记，我们也将评估这些基因与 褪黑激素水平。没有其他前瞻性队列研究可以提供更好的资源来回答这些问题 问题：在NHSII队列研究中，从1989年开始每两年评估一次夜班工作状态 从那时起，褪黑素水平已经在一组女性中进行了测量，并收集了大量的 DNA目前正在进行中，将提供1,108例乳腺癌病例的DNA及其1：3匹配的DNA 控制。这项研究的结果可能有助于确定哪些人更容易上夜班 根据他们的基因特征，他们比其他人更好。

Light exposure at night may have an adverse effect on breast cancer risk through suppression of melatonin, a hormone that is intimately linked to the circadian system and demonstrates cancer-protective effects. Observational studies have consistently associated night work with an increase in breast cancer risk. To date, nine candidate genes for human circadian dysrhythmias have been identified, and common mutations of four of those were associated with seasonal affective disorder, familial advanced sleep phase syndrome, and diurnal preference. In mice, loss of mPer2 function results in increased tumor development and deficiencies in DMAdamage responses. In humans, data, although still sparse, indicate a positive association between certain clock gene mutations and breast cancer risk. Thus, future investigations of the associations between breast cancer risk and circadian disruption, such as experienced by night workers, must take into consideration the role of clock genes. In this study, we propose to draw on the existing data and DMAsamples from the ongoing Nurses Health Study II (NHS II) to conduct a nested case-control study that evaluates associations of common variants in candidate genes of the circadian clock with breast cancer risk, as well as interactions with night shift work. We will assess how the nurses' breast cancer risk is influenced by different polymorphisms of clock genes and will characterize differences in these associations according to night work status of nurses. To further study the relationship between molecular rhythmicity and other markers of the circadian system, we will also assess the association of these genes with variations in melatonin levels. No other prospective cohort study can provide superior resources to answer these questions: in the NHSII cohort study, night shift work status has been assessed biennially from 1989 onwards, melatonin levels have been measured in a subgroup of women, and an extensive collection of DNA is currently under way that will provide DNA from 1,108 breast cancer cases and their 1:3 matched controls. The results from this study could help identify individuals who are more susceptible to night work than others, based on their genetic profile.