Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2024 Jan-Dec;16(1):2363012.
doi: 10.1080/19490976.2024.2363012. Epub 2024 Jun 11.

Association between gut microbiota and CpG island methylator phenotype in colorectal cancer

Pyoung Hwa Park  1   2 , Kelsey Keith  1   2 , Gennaro Calendo  2 , Jaroslav Jelinek  1   2   3 , Jozef Madzo  1   2   3 , Raad Z Gharaibeh  4   5 , Jayashri Ghosh  1 , Carmen Sapienza  1 , Christian Jobin  4 , Jean-Pierre J Issa  1   2   3
Affiliations

Association between gut microbiota and CpG island methylator phenotype in colorectal cancer

Pyoung Hwa Park et al. Gut Microbes. 2024 Jan-Dec.

Abstract

The intestinal microbiota is an important environmental factor implicated in CRC development. Intriguingly, modulation of DNA methylation by gut microbiota has been reported in preclinical models, although the relationship between tumor-infiltrating bacteria and CIMP status is currently unexplored. In this study, we investigated tumor-associated bacteria in 203 CRC tumor cases and validated the findings using The Cancer Genome Atlas datasets. We assessed the abundance of Bacteroides fragilis, Escherichia coli, Fusobacterium nucleatum, and Klebsiella pneumoniae through qPCR analysis and observed enrichment of all four bacterial species in CRC samples. Notably, except for E. coli, all exhibited significant enrichment in cases of CIMP. This enrichment was primarily driven by a subset of cases distinguished by high levels of these bacteria, which we labeled as "Superhigh". The bacterial Superhigh status showed a significant association with CIMP (odds ratio 3.1, p-value = 0.013) and with MLH1 methylation (odds ratio 4.2, p-value = 0.0025). In TCGA CRC cases (393 tumor and 45 adj. normal), bacterial taxa information was extracted from non-human whole exome sequencing reads, and the bacterial Superhigh status was similarly associated with CIMP (odds ratio 2.9, p < 0.001) and MLH1 methylation (odds ratio 3.5, p < 0.001). Finally, 16S ribosomal RNA gene sequencing revealed high enrichment of Bergeyella spp. C. concisus, and F. canifelinum in CIMP-Positive tumor cases. Our findings highlight that specific bacterial taxa may influence DNA methylation, particularly in CpG islands, and contribute to the development and progression of CIMP in colorectal cancer.

Keywords: Colorectal cancer; CpG island methylator phenotype; DNA methylation; Epigenetics; Gut microbiota.

PubMed Disclaimer

Conflict of interest statement

No potential conflict of interest was reported by the author(s).

Figures

Figure 1.
Figure 1.
Categorical analysis of hierarchical clustering of methylation data CIMP status of CRC patient tumor samples.
Figure 2.
Figure 2.
Enrichment of CRC-associated bacteria in CIMP-Positive CRC tumor samples.
Figure 3.
Figure 3.
Bacterial enrichment in CRC adjacent normal is associated with CIMP.
Figure 4.
Figure 4.
Validation of the CIMP classification method by DREAM using TCGA colon adenocarcinoma and rectum adenocarcinoma methylation array data set.
Figure 5.
Figure 5.
Discovery of CIMP-associated taxa in CRC tumor samples by 16S ribosomal RNA sequencing.
See this image and copyright information in PMC

References

    1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, Bray F.. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–18. doi:10.3322/caac.21660. - DOI - PubMed
    1. Talseth-Palmer BA. The genetic basis of colonic adenomatous polyposis syndromes. Hered Cancer Clin Pract. 2017;15(1). doi:10.1186/s13053-017-0065-x. - DOI - PMC - PubMed
    1. Islami F, Goding Sauer A, Miller KD, Siegel RL, Fedewa SA, Jacobs EJ, McCullough ML, Patel AV, Ma J, Soerjomataram I. et al. Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA Cancer J Clin. 2018;68(1):31–54. doi:10.3322/caac.21440. - DOI - PubMed
    1. Müller MF, Ibrahim AEK, Arends MJ. Molecular pathological classification of colorectal cancer. Virchows Arch. 2016;469(2):125–134. doi:10.1007/s00428-016-1956-3. - DOI - PMC - PubMed
    1. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP. CpG island methylator phenotype in colorectal cancer,” (in eng. Proc Natl Acad Sci U S A. 1999. Jul. 96(15):8681–8686. doi:10.1073/pnas.96.15.8681. - DOI - PMC - PubMed

Publication types