Grant Number:	1R01CA296006-01A1 Interpret this number
Primary Investigator:	Hullar, Meredith
Organization:	Fred Hutchinson Cancer Center
Project Title:	Distinctive Features of the Tumor-Associated Microbiome in Early-Onset Rectal Cancers: Elucidating the Microenvironment of an Emerging Disease
Fiscal Year:	2026

PROJECT SUMMARY / ABSTRACT Although overall incidence rates of colorectal cancer (CRC) in the United States (US) have been declining in recent decades, rates in younger adults have been steadily increasing since the mid-1990s. These observed increases in incidence are specific to early-onset cancers arising in the sigmoid colon and rectum (EORC). Thus, to better understand the basis for the observed rise in early-onset CRC, it is critical to focus on the distinct features and biology of EORC. Evidence points to a role of the intra-tumoral microbiome (including both bacteria and fungi) in CRC etiology, with suggested differences in microbial profiles by tumor site. While a few pathogenic candidate bacteria have been suggested in later-onset CRC (e.g., Fusobacterium nucleatum, pks+ Escherichia coli), there is a dearth of microbiome studies in early-onset CRC. This represents a key knowledge gap given that the composition of the microbiome changes with age, and temporal changes in environmental exposures over the last 60 years (e.g., aspects of diet) plausibly impact differences in composition of the gut microbiome across birth cohorts. The objective of this proposal is to elucidate factors underlying the rising incidence in early-onset CRC by focusing on tissue-associated microbial features that distinguish EORC, their connection to other tumor features, and their implications for outcomes. Building upon the resources of the Puget Sound Colorectal Cancer Cohort (PSCCC), we propose three aims to contrast and contextualize the intra-tumoral microbiome in EORC (N=218) as compared to the microbiome in later-onset sigmoid colon and rectal cancers (LORC, N=256) and early-onset proximal colon cancers (EOCC, N=127), with contrasts to the microbiome in colorectal tissue among cancer-free individuals accounting for variability in tissue site and age (N=100). In Aim 1, we will use 16S rRNA bacterial gene sequencing and 18S-5S rRNA fungal gene sequencing to identify bacterial and fungal candidates that distinguish the microbiome (1a) in EORC from that in LORC, (1b) in EORC from that in EOCC, and (1c) in tumors compared to colorectal tissue in cancer- free comparison participants, controlling for tissue site and age. In Aim 2, we will incorporate microbial data with existing data on tumor clinicopathologic factors (e.g., microsatellite instability status, stage at diagnosis) and histomorphological features (e.g., tumor:stroma ratio). Using deep learning (DL) approaches, we will identify integrative signatures that distinguish EORC from LORC and EOCC (2a). We will also examine how those signatures relate to disease survival (2b). In Aim 3, we will focus our assessment on microbial genes with a plausible role in cancer etiology pathways (i.e., cysteine desulfidase, nitrate reductase), to examine how the presence and quantity of those genes differs (3a) in the EORC intra-tumoral microbiome versus in LORC, (3b) in EORC vs. in EOCC, and (3c) in tumors vs. in colorectal tissue from cancer-free controls. Information generated by this study will deepen understanding of the role of the microbiome in emerging CRC incidence trends and identify intervenable microbial factors in early-onset cancers in the sigmoid colon and rectum.





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