||5R01CA217970-02 Interpret this number
||University Of Washington
||Bacterial Correlates of Colorectal Cancer Subgroups and Survival
PROJECT SUMMARY / ABSTRACT
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.
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