Limiting oxidative DNA damage reduces microbe-induced colitis-associated colorectal cancer

Thergiory Irrazabal, Bhupesh K. Thakur, Mingsong Kang, Yann Malaise, Catherine Streutker, Erin O. Y. Wong, Julia Copeland, Robert Gryfe, David S. Guttman, William W. Navarre and Alberto Martin ()
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Thergiory Irrazabal: University of Toronto
Bhupesh K. Thakur: University of Toronto
Mingsong Kang: University of Toronto
Yann Malaise: University of Toronto
Catherine Streutker: St. Michael’s Hospital
Erin O. Y. Wong: University of Toronto
Julia Copeland: University of Toronto
Robert Gryfe: Mount Sinai Hospital
David S. Guttman: University of Toronto
William W. Navarre: University of Toronto
Alberto Martin: University of Toronto

Nature Communications, 2020, vol. 11, issue 1, 1-14

Abstract: Abstract Inflammatory bowel disease patients have a greatly increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CRC), we test whether 8-oxoguanine mediates oncogenesis in a Lynch syndrome (MMR-deficient) model. We show that microbiota generates an accumulation of 8-oxoguanine lesions in MMR-deficient colons. Accordingly, we find that 8-oxoguanine is elevated in neoplastic tissue of Lynch syndrome patients compared to matched untransformed tissue or non-Lynch syndrome neoplastic tissue. While antioxidants reduce 8-oxoguanine, they do not reduce CRC in Lynch syndrome models. Hence, microbe-induced oxidative/nitrosative DNA damage play causative roles in inflammatory CRC models, but not in Lynch syndrome models.

Date: 2020
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DOI: 10.1038/s41467-020-15549-6

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