Tumor microbial biodiversity and microsatellite instability in colorectal cancer
7 affiliations
- 1Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington, United States of America
- 2Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America
- 3Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, Washington, United States of America
- 4Centre for Public Health Research, Massey University, Wellington, New Zealand
- 5Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
- 6Department of Pathology, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, United States of America
- 7Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America
Abstract
Background: Growing evidence links the gut microbiome to colorectal cancer (CRC) progression, with certain bacterial species enriched in specific molecular tumor subtypes. DNA mismatch repair deficiency in CRC, evidenced by the presence of microsatellite instability (MSI), has been consistently associated with a favorable prognosis, and may be related to certain aspects of the microbiome. Here, we examined the relationship between tumor microbial biodiversity and MSI status. Methods: Diagnostic tumor tissue samples were obtained from the Seattle site of the Colon Cancer Family Registry (SCCFR) and a companion study; both recruited patients diagnosed with incident CRC from 1998 to 2007. MSI status assessment and prokaryotic 16S rRNA gene sequencing was performed on the tumor tissue samples. We used an adaptive test of alpha-diversity (aMiAD) to estimate the association between microbial biodiversity and MSI status. We performed differential abundance analysis with ANCOM-BC to identify enriched genera in tumor tissue, based on dichotomized MSI status. Analyses were adjusted for age, sex, smoking history, and tumor location (N = 632). Results: The adaptive aMiAD effect estimate was −1.08 (p = 0.29), suggesting that MSI-high tumors had lower estimated alpha-diversity, though this difference was not statistically significant. We identified 20 differentially abundant genera in CRC tumors according to MSI status, with 8 enriched genera and 12 depleted genera in MSI-high tumors. The most strongly enriched genera in MSI-high tumors were Gemella and Lawsonella, while Sporolactobacillaceae and Cloacibacterium were the most strongly depleted. Fusobacterium was enriched in MSI-high tumors only after subsetting the genus to Fusobacterium nucleatum specific sequences. Conclusions: We did not detect a statistically significant association between the adaptive alpha-diversity measure and MSI status, though individual measures concordantly estimated a depletion of alpha-diversity in the MSI-high tumors. We found evidence of differential abundance of certain genera dependent on MSI status, including several novel associations.
Related
- Distinct genomic landscapes of mismatch-repair deficiency (dMMR)/microsatellite instability-high (MSI-H) gastrointestinal (GI) cancer depending on tumor mutation burden (TMB) levels.
- Systemic antibody repertoires target specific microbial antigens in patients with colorectal cancer
- Integrated Multiomics and Functional Validation Identify CLSPN as a Central Integrator of Genomic Instability and Immune Remodeling in Colorectal Cancer
- Clinical, Pathological, and Molecular Characteristics in Colorectal Cancer
- Meat and colorectal cancer: Gut microbiota may play a major role
BibTeX
@article{mendall2026tumor,
title = {{Tumor microbial biodiversity and microsatellite instability in colorectal cancer}},
author = {Calen Mendall and Meredith A. J. Hullar and Keith R. Curtis and Courtney M. Hill and Claire E. Thomas and Ningxin Ma and Timothy W. Randolph and Rachel C. Malen and Adriana M. Reedy and Scott LaBrie and John D. Potter and Shuji Ogino and Polly A. Newcomb and Amanda I. Phipps},
journal = {PLOS One},
year = {2026},
month = sep,
doi = {10.1371/journal.pone.0359555},
url = {https://doi.org/10.1371/journal.pone.0359555},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Tumor microbial biodiversity and microsatellite instability in colorectal cancer
AU - Calen Mendall
AU - Meredith A. J. Hullar
AU - Keith R. Curtis
AU - Courtney M. Hill
AU - Claire E. Thomas
AU - Ningxin Ma
AU - Timothy W. Randolph
AU - Rachel C. Malen
AU - Adriana M. Reedy
AU - Scott LaBrie
AU - John D. Potter
AU - Shuji Ogino
AU - Polly A. Newcomb
AU - Amanda I. Phipps
PY - 2026
DA - 2026/09/25
JO - PLOS One
DO - 10.1371/journal.pone.0359555
UR - https://doi.org/10.1371/journal.pone.0359555
AB - Background: Growing evidence links the gut microbiome to colorectal cancer (CRC) progression, with certain bacterial species enriched in specific molecular tumor subtypes. DNA mismatch repair deficiency in CRC, evidenced by the presence of microsatellite instability (MSI), has been consistently associated with a favorable prognosis, and may be related to certain aspects of the microbiome. Here, we examined the relationship between tumor microbial biodiversity and MSI status. Methods: Diagnostic tumor tissue samples were obtained from the Seattle site of the Colon Cancer Family Registry (SCCFR) and a companion study; both recruited patients diagnosed with incident CRC from 1998 to 2007. MSI status assessment and prokaryotic 16S rRNA gene sequencing was performed on the tumor tissue samples. We used an adaptive test of alpha-diversity (aMiAD) to estimate the association between microbial biodiversity and MSI status. We performed differential abundance analysis with ANCOM-BC to identify enriched genera in tumor tissue, based on dichotomized MSI status. Analyses were adjusted for age, sex, smoking history, and tumor location (N = 632). Results: The adaptive aMiAD effect estimate was −1.08 (p = 0.29), suggesting that MSI-high tumors had lower estimated alpha-diversity, though this difference was not statistically significant. We identified 20 differentially abundant genera in CRC tumors according to MSI status, with 8 enriched genera and 12 depleted genera in MSI-high tumors. The most strongly enriched genera in MSI-high tumors were Gemella and Lawsonella, while Sporolactobacillaceae and Cloacibacterium were the most strongly depleted. Fusobacterium was enriched in MSI-high tumors only after subsetting the genus to Fusobacterium nucleatum specific sequences. Conclusions: We did not detect a statistically significant association between the adaptive alpha-diversity measure and MSI status, though individual measures concordantly estimated a depletion of alpha-diversity in the MSI-high tumors. We found evidence of differential abundance of certain genera dependent on MSI status, including several novel associations.
SN - 1932-6203
ER -