Gut Microbiome, Antibiotic Use & Colon Cancer Recurrence

项目总结/摘要 尽管在预防、筛查和治疗方面取得了进展，但结直肠癌（CRC）仍然是第三大癌症。 在男性和女性中，常见的癌症和第二大癌症死亡原因是 美方目前生活在美国的近120万CRC幸存者面临着不良CRC结局的风险。的 大量的《儿童权利公约》幸存者，加上《儿童权利公约》的巨大财政负担， 确定生物标志物，以预测CRC患者的复发，可用于指导临床决策 关于治疗和监视的问题目前还没有确定的生物标志物来识别结肠癌， 复发的可能性很大人类肠道包含最大的细菌生态系统（肠道微生物组）， 人体然而，无论肠道微生物组（直接或间接通过细菌代谢物）是否 与CRC复发的关系尚不清楚。最后，考虑到抗生素的流行， 和质子泵抑制剂（PPI）的人群，以及它们对肠道微生物组的影响， 抗生素和PPI的使用与CRC复发需要进行调查。为了弥补这些知识差距， 一项拟议的研究旨在生成高通量16 S测序数据，以研究 肿瘤特异性肠道微生物谱与结肠癌复发。这项研究将分两个阶段进行。 在发现阶段，我们将确定与283例结肠癌早期复发相关的细菌谱 II/III期患者，具有可用的快速冷冻肿瘤组织。在验证阶段， 将在600名II/III期结肠癌患者的独立组中进行评估。 最后，利用丹麦医学、临床和人口登记处的大量高质量数据， 我们将研究诊断前抗生素治疗和质子泵抑制剂（PPI）的使用是否相关， 在丹麦，2001年至2012年间诊断的> 21，000名CRC患者中复发。这些发现 我们的研究将有助于鉴定结肠癌复发的潜在肿瘤特异性生物标志物， 并阐明肠道微生物组在结肠癌进展中的可能作用。

PROJECT SUMMARY/ABSTRACT Despite advances in prevention, screening, and treatment, colorectal cancer (CRC) remains the 3rd most commonly diagnosed cancer and the 2nd leading cause of cancer deaths among men and women combined in the US. Nearly 1.2 million CRC survivors currently living in the US are at risk of adverse CRC outcomes. The large number of CRC survivors coupled with the considerable financial burden of CRC makes it critical to identify biomarkers to predict recurrence among CRC patients that can be used to guide clinical decisions regarding treatment and surveillance. Currently there are no definitive biomarkers to identify colon cancer with a high likelihood to recur. The human gut contains the largest bacterial ecosystem (gut microbiome) in the human body. However, whether the gut microbiome (directly or indirectly via bacterial metabolites) is associated with CRC recurrence is unknown. Lastly, given the prevalence, and often overuse, of antibiotics and proton pump inhibitors (PPIs) in the population, and their effects on the gut microbiome, the association of antibiotic and PPI use with CRC recurrence needs to be investigated. To address these knowledge gaps, the proposed study seeks to generate high-throughput 16S sequencing data to investigate the associations of tumor-specific gut microbial profiles with colon cancer recurrence. This study will be conducted in two phases. In the discovery phase, we will identify bacterial profiles associated with early recurrence in 283 colon cancer stage II/III patients with available snap frozen tumor tissue. In the validation phase, top bacterial candidates from our discovery phase will be evaluated in an independent set of 600 stage II/III colon cancer patients. Finally, taking advantage of a wealth of high-quality data in Danish medical, clinical, and population registries, we will examine whether pre-diagnostic antibiotic therapy and proton pump inhibitor (PPI) use are associated with recurrence among >21,000 CRC patients diagnosed between 2001 and 2012 in Denmark. The findings of our study will contribute to identification of potential tumor-specific biomarkers of colon cancer recurrence, and clarify the possible roles of the gut microbiome in colon cancer progression.