A Prospective Investigation of the Oral Microbiome and Pancreatic Cancer

 描述(申请人提供)：胰腺癌是一种高度致命的疾病(五年存活率只有6%)，目前几乎没有机会进行有意义的一级或二级预防。它是美国男性和女性癌症死亡的第四大常见原因。非裔美国人背负着美国最高的胰腺癌发病率和死亡率，比发病率第二高的非西班牙裔白人高出约30%。目前对可能有助于初级预防或确定高危人群进行潜在筛查或干预的因素缺乏了解，这是改善这种癌症糟糕前景的主要障碍。越来越多的证据，包括目前应用产生的试点结果，表明共生和致病口腔细菌可能在胰腺癌的发展中发挥作用。如果是这样，如果能够确定口腔微生物区系的相关特征，这可能是一个 我们预防胰腺癌的能力取得了重大突破，因为口腔生态是可以改变的。我们将新的微生物基因测序和生物信息学方法的出现视为研究口腔微生物群落如何可能对胰腺癌风险和差异做出贡献的基本机会。利用南方社区队列研究和黑人妇女健康研究这两项前瞻性流行病学研究的现有资源，我们建议通过对口腔微生物群和胰腺癌进行全面调查，大幅推进这一新的调查路线。我们将在已建立的父母队列中这样做，这些队列处于独特的位置，包括非裔美国人(以及欧洲裔美国人)，并解决口腔微生物组中潜在的种族差异，这些差异是非裔美国人胰腺癌额外负担的驱动因素。在125例胰腺癌病例和450例对照的嵌套病例对照研究中，使用诊断前口腔漱口样本，我们将使用高产量的基因组鸟枪测序来表征和比较病例和对照的口腔微生物群，假设微生物丰度、多样性和/或功能在这些组之间将有所不同(目标1)。在对照组中，我们还将评估口腔微生物组中的种族差异，并确定可能解释非裔美国人胰腺癌发病率增加的任何差异(目标2)。我们将进一步确定公认的、可修改的胰腺癌危险因素(吸烟、肥胖、红肉和加工肉类消费、饮酒、2型糖尿病)与口腔微生物组属性之间的联系，并评估这些暴露是否与高风险口腔微生物组特征有关(目标3)。这项研究可能会产生直接和长期的重大影响，为新的机制研究以及转化活动打开大门，包括操纵微生物组来预防癌症，开发与微生物组相关的治疗方法，并最终减少胰腺癌的发病率和差异。

 DESCRIPTION (provided by applicant): Pancreatic cancer is a highly fatal disease (five-year survival rate of only 6%) with virtually no current opportunities for meaningful efforts towards primary or secondary prevention. It is the fourth most common cause of cancer death for both men and women in the US. African Americans are disproportionately burdened with the highest pancreatic cancer incidence and mortality rates in the US - about 30% higher than the group with the next highest rates, non-Hispanic whites. The current lack of knowledge on factors that could be useful for primary prevention or for identifying high-risk groups for potential screening or intervention is a major impediment to improving the poor outlook for this cancer. Evidence has been mounting, including pilot results generated for the current application, that commensal and pathogenic oral bacteria may play a role in pancreatic cancer development. If this is the case, and if the relevant characteristics of the oral microbiota can be identified, this could be a major breakthrough in our ability to prevent pancreatic cancer, because the oral ecology is modifiable. We see the emergence of new microbial gene sequencing and bioinformatics methods as a fundamental opportunity to study how oral microbial communities may contribute to pancreatic cancer risk and disparities. Leveraging the existing resources of two prospective, epidemiologic studies, the Southern Community Cohort Study and the Black Women's Health Study, we propose to substantially advance this emerging line of enquiry by conducting a comprehensive investigation of the oral microbiome and pancreatic cancer. We will do so within established parent cohorts that are uniquely situated to include African Americans (as well as European Americans) and to address potential racial differences in the oral microbiome as drivers of the excess burden of pancreatic cancer among African Americans. In a nested case-control study of 125 incident pancreatic cancer cases and 450 controls, using pre-diagnostic oral rinse samples, we will employ high-output genomic shotgun sequencing to characterize and compare the oral microbiome of cases and controls, hypothesizing that microbial abundance, diversity, and/or function will differ between these groups (Aim 1). Among the controls, we will also evaluate racial differences in the oral microbiome and identify any differences that may explain the increased incidence of pancreatic cancer among African Americans (Aim 2). We will further determine the association between recognized, modifiable risk factors for pancreatic cancer (cigarette smoking, obesity, red meat and processed meat consumption, alcohol consumption, type 2 diabetes) and oral microbiome attributes, and evaluate whether these exposures are associated with high-risk oral microbiome profiles (Aim 3). This study could have both immediate and long-term major impact by opening the doors for new mechanistic research as well as translational activities including manipulating the microbiome for cancer prevention, developing therapies related to the microbiome, and ultimately reducing the incidence of, and disparities in, pancreatic cancer.