Distinct intratumoral microbiome of young-onset and average-onset colorectal cancer

Shimoli V Barot; Naseer Sangwan; Kanika G Nair; Stephanie L Schmit; Shao Xiang; Suneel Kamath; David Liska; Alok A Khorana

doi:10.1016/j.ebiom.2024.104980

Distinct intratumoral microbiome of young-onset and average-onset colorectal cancer

EBioMedicine. 2024 Feb:100:104980. doi: 10.1016/j.ebiom.2024.104980. Epub 2024 Feb 1.

Authors

Shimoli V Barot¹, Naseer Sangwan², Kanika G Nair³, Stephanie L Schmit⁴, Shao Xiang⁵, Suneel Kamath³, David Liska⁶, Alok A Khorana⁷

Affiliations

¹ Cleveland Clinic Taussig Cancer Institute, Department of Hematology-Oncology, USA.
² Shared Laboratory Resources (SLR), Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Cardiovascular and Metabolic Sciences, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
³ Cleveland Clinic Taussig Cancer Institute, Department of Hematology-Oncology, USA; Case Comprehensive Cancer Center, Cleveland, OH, USA; Center for Young-Onset Colorectal Cancer, Cleveland Clinic, Cleveland, OH, USA.
⁴ Center for Young-Onset Colorectal Cancer, Cleveland Clinic, Cleveland, OH, USA; Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Population and Cancer Prevention Program, Case Comprehensive Cancer Center, Cleveland, OH, USA.
⁵ Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA.
⁶ Case Comprehensive Cancer Center, Cleveland, OH, USA; Center for Young-Onset Colorectal Cancer, Cleveland Clinic, Cleveland, OH, USA; Department of Cancer Biology, Lerner Research Institute, Cleveland Clinic, Cleveland, OH, USA; Department of Colorectal Surgery, Digestive Disease and Surgery Institute, Cleveland Clinic, Cleveland, OH, USA.
⁷ Cleveland Clinic Taussig Cancer Institute, Department of Hematology-Oncology, USA; Case Comprehensive Cancer Center, Cleveland, OH, USA; Center for Young-Onset Colorectal Cancer, Cleveland Clinic, Cleveland, OH, USA. Electronic address: khorana@ccf.org.

Abstract

Background: The unexplained rise of young-onset CRC (yoCRC, age <50 years) is of concern. Evidence suggests that microbial dysbiosis may be a contributing factor, but the tumor microbial profile of yoCRC in comparison to average-onset CRC (aoCRC, age >60) has not been fully investigated.

Methods: 16S rRNA amplicon sequencing was performed in tumor and paired adjacent non-malignant fresh frozen tissue specimens prospectively collected from 136 yoCRC and 140 aoCRC patients. Phyloseq, microbiomeSeq, metagenomeSeq, and NetComi were utilized for bioinformatics analysis. Statistical tests included Fisher's exact test, ANOVA, PERMANOVA with Bonferroni correction, linear regression, and Wilcoxon test. p-value <0.05 was considered statistically significant.

Findings: yoCRC patients were more likely to have left-sided (72.8 vs. 54.3%), rectal (36.7% vs. 25%), and stage IV (28% vs. 15%) tumors. yoCRC tumors had significantly higher microbial alpha diversity (p = 1.5 × 10^-5) and varied beta diversity (R2 = 0.31, p = 0.013) than aoCRC tumors. yoCRC tumors were enriched with Akkermansia and Bacteroides, whereas aoCRC tumors showed greater relative abundances of Bacillus, Staphylococcus, Listeria, Enterococcus, Pseudomonas, Fusobacterium, and Escherichia/Shigella. Akkermansia had a predominantly negative correlation with the microbial communities in yoCRC tumors. yoCRC and aoCRC tumors had distinct microbial profiles associated with tumor location, sidedness, stage, and obesity. Fusobacterium (R2 = -0.23, p = 0.001) and Akkermansia (R2 = 0.05, p = 0.001) abundance correlated with overall survival in yoCRC.

Interpretation: Our study provides a comprehensive understanding of the microbial perturbations in yoCRC tumors. We identify microbial candidates that may highlight a distinct pathogenesis of yoCRC and serve as preventive, diagnostic, and therapeutic targets.

Funding: Sondra and Stephen Hardis Chair in Oncology Research (A.A.K.).

Keywords: 16S; Colorectal cancer; Dysbiosis; Early-onset; Microbiome; Young-onset.

MeSH terms

Bacteroides
Colorectal Neoplasms* / pathology
Humans
Microbiota* / genetics
Middle Aged
RNA, Ribosomal, 16S / genetics
Rectum

Substances

RNA, Ribosomal, 16S