Worldwide, colorectal cancer (CRC) is a common malignancy and develops through accumulation of colonic epithelial cell mutations that stimulate transition of normal mucosa to adenocarcinoma. About 5 percent of CRC occurs in individuals having inherited mutations. One such condition, familial adenomatous polyposis (FAP), is caused by germline mutations in the APC tumor suppressor gene –– which cause the gene to stop suppressing cancer, thereby enhancing tumorigenesis. Individuals with FAP are born with their first mutation (occurring in one of the two alleles of the chromosome pair), making them more prone to developing CRC if a second mutation in the APC gene occurs. This phenomenon, known as the “two-hit” hypothesis, was first proposed by geneticist/epidemiologist Alfred Knudson in 1971.
As somatic mutations accumulate in patients with FAP, they develop hundreds to thousands of colorectal polyps. The onset and frequency of polyp formation within families bearing the same APC gene mutation varies substantially, i.e. why do some polyps rapidly proceed on to tumors whereas others do not? This suggests that additional factors contribute to disease onset, including components of the microbiome. As these GEITP pages have continued to harp on, the colon contains trillions of bacteria. These bacteria are separated from the colonic epithelium by a dense mucus layer. This mucus layer promotes tolerance to foreign antigens by limiting bacterial–epithelial cell contact and, thus, mucosal inflammatory responses. In contrast, bacterial gaps occur into the colonic mucus layer where, in some individuals, biofilm formation fosters chronic mucosal inflammation.
In FAP patients, authors [see attached article] identified patchy bacterial biofilms composed predominantly of Escherichia coli and Bacteroides fragilis. Genes for colibactin (clbB) and Bacteroides fragilis toxin (bft), encoding secreted oncotoxins, were highly enriched in FAP patients’ colonic mucosa compared to that in healthy individuals. Tumor-prone mice –– co-colonized with E. coli (expressing colibactin), and enterotoxigenic B. fragilis –– showed increased interleukin-17 (IL17) in colon and DNA damage in colonic epithelium with faster tumor onset and greater mortality, compared to mice with either bacterial strain alone. These data suggest an unexpected link between early neoplasia of the colon and tumorigenic bacteria that are synergistic in action.
Science 2 Feb 2o18; 359: 592–597