Circadian Disruption and Risk of Prostate Cancer in a Multiethnic Cohort

 描述(申请人提供)：全球每年有超过110万名男性被诊断患有前列腺癌，并导致30万人死于癌症。对于死亡率显著上升的非裔美国人来说，这一影响尤为深远。这些明显的前列腺癌差异的来源尚不清楚。我们的应用侧重于在种族/民族多样化的队列中扰乱昼夜节律和前列腺癌风险。其基本原理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，并提出了一种通过扰乱昼夜节律来实现的机制。我们从白人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，包括褪黑激素降低、睡眠中断增加和昼夜节律基因变异，都与晚期前列腺癌的高风险有关。与其他种族的男性相比，非洲裔美国男性改变了昼夜节律，褪黑激素水平较低。我们提出了一项关于昼夜节律紊乱的综合性分子流行病学研究，以调查昼夜节律紊乱与前列腺癌风险之间的关系，以及昼夜节律紊乱在多大程度上解释了种族差异。这项研究将嵌套在预期的多种族队列(MEC)中的男性中，该队列自1993年开始，包括拉丁裔、非裔美国人、夏威夷人、日本人和白人男性。我们将在2000年至2014年确诊的1,648例前列腺癌患者(N=801例晚期/致命疾病)和3,296名匹配的对照组中，检测诊断前尿6-硫氧基黑素，褪黑素的主要代谢物。我们将使用PRE- 现有的数据来自全基因组关联研究，以调查昼夜节律基因的遗传变异和已知的前列腺癌风险基因与6-硫氧基黑素水平的关系。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，一个主要目标是按种族/民族正式比较和对比这些联系。认为昼夜节律紊乱是前列腺癌风险因素的假设是有希望的，但解决起来有些肤浅；关于晚期疾病的少数研究只有很少的数据，而且还没有在种族/民族多样化的人群中进行研究。然而，在拟议的研究中对这一新的假设进行仔细的调查，可以大大增加我们对前列腺癌，特别是侵袭性疾病的可变性风险因素的了解，并特别确定导致差异的风险因素。这项研究的结果具有很高的转化性(可能通过交替的褪黑素水平和睡眠模式)，并可能阐明一级和二级预防的机会。此外，利用大量已建立的队列和预先存在的遗传数据，使这项研究变得高效和具有成本效益。

 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.