Clock Genes, Night Work, and Breast Cancer Risk

描述（由申请人提供）：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，褪黑激素是一种与昼夜节律系统密切相关的激素，具有癌症保护作用。观察性研究一直将夜班与乳腺癌风险的增加联系起来。迄今为止，已经确定了9个人类昼夜节律紊乱的候选基因，其中4个基因的常见突变与季节性情感障碍、家族性睡眠阶段提前综合征和昼夜偏好有关。在小鼠中，mPer2功能的丧失导致肿瘤发展增加和DMA损伤反应不足。在人类中，虽然数据仍然很少，但表明某些时钟基因突变与乳腺癌风险之间存在正相关。因此，未来对乳腺癌风险与昼夜节律中断之间关系的调查，如夜班工人的经历，必须考虑到生物钟基因的作用。在这项研究中，我们建议利用正在进行的护士健康研究II （NHS II）的现有数据和DMA样本进行巢式病例对照研究，评估生物钟候选基因的常见变异与乳腺癌风险的关系，以及与夜班工作的相互作用。我们将评估时钟基因的不同多态性对护士乳腺癌风险的影响，并根据护士的夜班状态来描述这些关联的差异。为了进一步研究分子节律性和其他昼夜节律系统标志物之间的关系，我们还将评估这些基因与褪黑激素水平变化的关系。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：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，在一个妇女亚组中测量褪黑激素水平，目前正在广泛收集DNA，将提供1108例乳腺癌病例及其1:3匹配对照的DNA。这项研究的结果可以根据基因特征来帮助识别那些比其他人更容易夜班的人。

DESCRIPTION (provided by applicant): 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 DMA damage 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 DMA samples 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.