The human gut is home to a complex ecosystem of hundreds of bacterial species. Beyond its critical role in facilitating and promoting healthy digestive and immune function, that ecosystem is increasingly recognized to impact many other aspects of health ? sometimes adversely. In particular, recent evidence has suggested that specific gut bacteria, or imbalances in gut bacterial populations, could play a role in the initiation and progression of colorectal cancer (CRC). Among such bacteria, enrichment of Fusobacterium nucleatum has been most commonly implicated in CRC. However, other aspects of the gut bacterial community structure and balance could plausibly contribute to the natural history of CRC. Improved understanding as to the impact of the gut bacterial community on CRC could generate new opportunities for CRC prevention, early detection, and treatment. Attaining such understanding, however, requires consideration for the fact that CRC is a heterogeneous disease: CRC subgroups based on tumor attributes (e.g., anatomic site, deficient DNA mismatch repair) have been associated with distinct etiologic pathways and differing prognosis. Therefore, the factors driving the natural history of these CRC subgroups could plausibly be expected to differ. The objective of this study is to identify differences in patterns of bacterial enrichment and community structure in CRC across tumor subgroups of etiologic and prognostic significance, and to assess the impact of those differences on CRC survival.
In Aim 1, we will refine current understanding as to the role of F. nucleatum in CRC by identifying differences in the distribution of F. nucleatum enrichment across tumor subgroups defined by clinicopathologic (e.g., stage at diagnosis) and molecular attributes (e.g., BRAF-mutation status, serrated-like subtype).
In Aim 2, we will expand our evaluation of the gut bacterial community to consider broader differences in the balance of bacterial taxa (2a), as well as differences in bacterial diversity within (2b) and between (2c) tumor subgroups. Lastly, in Aim 3, we will evaluate the relationship between aspects of gut bacterial community structure and CRC survival. In pursuit of these Aims, we will leverage the resources of the Puget Sound Colorectal Cancer Cohort (PSCCC): a population-based study of individuals with incident invasive CRC for whom follow-up for survival is ongoing, epidemiologic data are available, and numerous tumor attributes have been assayed. Through this project, we will conduct targeted candidate (i.e., F. nucleatum-specific) and global (i.e., 16S rRNA gene sequencing) assays to characterize the gut bacterial community in colorectal tumors and matched normal colon tissues from 1,250 CRC cases participating in the PSCCC. Adding these data to the PSCCC will provide an important opportunity to comprehensively investigate the relationship of the gut bacterial ecosystem to CRC subgroups of etiologic significance, and to CRC survival. Insights gained through this study could ultimately inform more targeted CRC surveillance strategies and motivate the development of antibiotic or probiotic CRC therapies and chemopreventive agents.
/ RELEVANCE The bacterial community of the human gut has been suggested to play a role in the development and progression of colorectal cancer. In this project, we will identify differences in the composition of the gut bacterial community across etiologically-distinct subgroups of colorectal cancer, and will assess the impact of those differences on cancer survival. Knowledge gained from this study may inform future strategies for the early detection and control of colorectal cancer.
