Project 3: Racial and ethnic differences in the intra-tumoral microbiome: Impact on colorectal cancer mortality and clinicopathologic correlates

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) incidence and mortality vary greatly by race and ethnicity in the United States (US). Alaska Native people have among the highest reported rates of CRC in the world; African American people also shoulder an elevated burden of CRC compared to other groups in the US. This disproportionate burden of CRC

is marked by differences in the distribution of clinicopathologic factors (e.g., tumor site, age at CRC onset, consensus molecular subtypes) by race and ethnicity, which also has implications for outcomes. In exploring factors that may contribute to these observed disparities, minimal consideration has been paid to the potential

contribution of the microbiome. The presence of a gut microbial community is common across all human populations, but the composition of that community varies greatly – by sex, diet, and race and ethnicity. The composition of the gut microbiome has plausible implications for a variety of pertinent health outcomes, including

CRC. Increasing evidence indicates that specific gut bacteria, or imbalances in bacterial populations, could play a role in the natural history of CRC. Prior studies have implicated a small number of candidate bacteria (e.g., Fusobacterium nucleatum; Fn) as contributors to CRC etiology and survival; however, our early studies suggest

these candidates are unlikely to be significant contributors to CRC disparities. Instead, we are identifying novel candidate bacteria that are disproportionately prevalent in tumors among Alaska Native and African American patients with CRC. The objective of this project is to test our overarching hypothesis that specific racial and

ethnic differences in the tumor microbiome contribute to disparities in CRC attributes and outcomes. In pursuit of this objective, we will leverage and build upon existing biospecimen and data resources, infrastructure, and preliminary findings accumulated through the Translational Research Program in Colorectal Cancer Disparities

(TRPCD). In Aim 1, using quantitative digital droplet PCR (ddPCR) assays, we will: (1a) test for differences in the prevalence and abundance of novel candidate bacteria in colorectal tumors across four racial and ethnic groups (Alaska Native, African American, Hispanic, and non-Hispanic White patients with CRC), and (1b) test

for associations with risk of lethal CRC overall and within racial and ethnic groups. For Aim 2, we will expand our evaluation of (2a) these novel candidates and (2b) microbial 16S rRNA gene sequencing (16S rRNAseq) data to examine relationships with clinicopathologic factors, with a focus on attributes that differ in their

distribution across racial and ethnic groups and have implications for outcomes. In Aim 3, we will use artificial intelligence, such as machine learning strategies, to identify tumor-associated microbial signatures in CRC associated with CRC-specific mortality and will assess differences in the distribution of those signatures by race

and ethnicity. Integration of the results from our aims can be used to inform more targeted cancer treatment strategies, particularly in understudied populations experiencing the greatest burden of CRC.