Circadian Disruption and Risk of Prostate Cancer in a Multiethnic Cohort

 描述（由申请人提供）：全球有超过110万男性被诊断患有前列腺癌，每年导致30万例癌症特异性死亡。这一影响对非洲裔美国男性尤其深远，他们的死亡率显著增加。这些前列腺癌差异的来源尚不清楚。我们的应用程序集中在破坏昼夜节律和前列腺癌的风险，在种族/民族多样化的队列。理由是基于国际癌症研究机构将夜班工作归类为可能的人类致癌物，并提出了通过昼夜节律紊乱的机制。我们从白色男性队列中获得的初步数据显示，昼夜节律紊乱的几个关键组成部分，包括低褪黑激素、睡眠中断增加和昼夜节律基因的变异，都与晚期前列腺癌的高风险有关。与其他种族的男性相比，非洲裔美国男性的昼夜节律发生了改变，褪黑激素水平较低。我们提出了一个昼夜节律紊乱的综合分子流行病学研究，以调查昼夜节律紊乱和前列腺癌风险之间的关联，以及昼夜节律紊乱在多大程度上解释了种族差异。 该研究将在前瞻性多种族队列（MEC）的男性中进行，自1993年以来一直在进行，包括拉丁裔、非裔美国人、夏威夷人、日本人和白色男性。我们将测量2000年至2014年诊断的1，648例前列腺癌病例（N=801例晚期/致命性疾病）和3，296例匹配对照中的诊断前尿6-硫酸酯基褪黑激素（褪黑激素的主要代谢产物）。我们将使用预- 来自全基因组关联研究的现有数据，以调查昼夜节律基因和已知前列腺癌风险基因座中的遗传变异与6-硫酸酯基褪黑激素水平。由于肥胖会损害昼夜节律，我们将使用人体测量数据来探索肥胖和前列腺癌之间的联系在多大程度上是通过改变昼夜节律来驱动的。对于所有分析，主要目标是按人种/种族正式比较和对比相关性。 昼夜节律紊乱是前列腺癌的一个危险因素，这一假设是有希望的，但已经解决了一些肤浅的;只有稀疏的数据，从少数研究的先进的疾病，并没有研究已在种族/民族多样化的人口。然而，在拟议的研究中对这一新假设的仔细调查可以大大增加我们对前列腺癌可改变的风险因素的理解，特别是对于侵袭性疾病，并特别确定导致差异的风险因素。这项研究的结果是高度转化的（可能通过交替的褪黑激素水平和睡眠模式），并可能阐明初级和二级预防的机会。此外，利用具有预先存在的遗传数据的大型既定队列使这项研究非常有效和具有成本效益。

 DESCRIPTION (provided by applicant): More than 1.1 million men are diagnosed with prostate cancer globally and causing 300,000 cancer-specific deaths each year. The impact is particularly profound for African-American men who suffer significantly increased mortality rates. The sources of these substantial prostate cancer disparities are unclear. Our application focuses on disruption of circadian rhythms and prostate cancer risk in a racially/ethnically diverse cohort. The rationale is based on the classification of nightshift work as a probable human carcinogen by the International Agency for Research on Cancer, with a proposed mechanism through circadian disruption. Our preliminary data from cohorts of white men show that several key components of circadian disruption, including low melatonin, increased sleep disruption, and variation in circadian genes, all are linked with with higher risk of advanced prostate cancer. African-American men have altered circadian rhythms and low melatonin compared to men of other races. We propose an integrative molecular epidemiology study of circadian disruption to investigate the association between circadian disruption and prostate cancer risk, and the extent to which circadian disruption explains racial disparities. The study will be nested among men in the prospective Multiethnic Cohort (MEC), ongoing since 1993 and including Latino, African-American, Hawaiian, Japanese and white men. We will measure pre-diagnostic urinary 6-sulfatoxymelatonin, the primary metabolite of melatonin, among 1,648 prostate cancer cases (N=801 with advanced/fatal disease) diagnosed 2000 to 2014 and 3,296 matched controls. We will use pre- existing data from genome-wide association studies to investigate genetic variants in circadian genes and known prostate cancer risk loci with 6-sulfatoxymelatonin levels. Because obesity impairs circadian rhythm, we will use anthropometric data to explore the extent to which the link between obesity and prostate cancer is driven through altered circadian rhythm. For all analyses, a primary goal is to formally compare and contrast the associations by race/ethnicity. The hypothesis that disruption of circadian rhythms is a risk factor for prostate cancer is promising, but has been addressed somewhat superficially; there are only sparse data from the few studies of advanced disease and no study has been conducted within a racially/ethnically diverse population. However, the careful investigation of this novel hypothesis in the proposed study could substantially increase our understanding of modifiable risk factors for prostate cancer, especially for aggressive disease, and also specifically identify risk factors that contribute to disparities. The results of this study are highly translational (potentially by alterng melatonin levels and sleep patterns), and could illuminate opportunities for primary and secondary prevention. Moreover, the utilization of a large established cohort with pre-existing genetic data makes this study highly efficient and cost-effective.