An exploration of intestinal bacterial biofilms in Lynch syndrome patients as disease markers for colorectal cancer

Colorectal cancer (CRC) affects 1.2 million people worldwide, of which 15% is
due to inherited genetic mutations. Lynch syndrome, caused by germ line defects
in one of the mismatch repair genes MLH1, MSH2, PMS2 or MSH6, frequently leads
to CRC (25-70%), endometrial cancer (25-70%) and, to a lesser extent, cancers
of the small bowel, stomach, ovary, ureter, bladder and hepatobiliary tract.
Lynch patients often develop recurrent colorectal tumors, making them an ideal
study group to prospectively analyze the development of adenomas.
Interestingly, some Lynch patients have a very high risk on developing
recurrent colorectal tumors, whilst some Lynch patients seem to be at a very
low risk. For surveillance of the development of colorectal tumors in Lynch
patients it is important to differentiate between the low and the high risk
patients.

Lynch-related tumors mostly develop in the ascending right side of the colon
(70-85%). Strikingly, it was recently discovered that dense bacterial biofilms
and invasive bacteria occur in the colonic mucosa of 87% of right-sided
colorectal cancer (CRC) patients, versus only 11% of left-sided CRC patients
and 13% of healthy controls. These biofilms could be identified both on tumors
and on the adjacent normal tissue. This is particularly relevant since recent
evidence showed that the intestinal microbiota is critically involved in CRC
pathogenesis. We hypothesize that biofilms host pathogenic bacteria and can
thereby contribute to CRC development. We think that biofilms may help to
differentiate between Lynch patients who are at high risk of developing CRC and
which ones are at low risk. In this study, we aim to determine whether biofilms
are present before CRC development and whether they can predict CRC development
in an early stage.

Extra biopties from colon mucosa will be collected from both Lynch syndrome
patients or control patients that are already scheduled for a colonoscopy.
These biopties will be studied for the presence of biofilms with modern
microscopy techniques. Subsequently, we will use these results to determine
whether patients with biofilms develop tumors more frequently. Additionally,
will also study the effect of biofilms on the mucosal barrier and oncogenesis
markers. Lastly, we aim to identify which bacteria are present within the
biofilms and study the functions and/or pathogenicity of these bacteria.

There is a minimal risk for bleeding associated with taking biopsies during
colonoscopy. The perforation risk after taking biopsies is negligible. The risk
for bleeding (about 2%) or perforation (about 0.01 to 0.1 %) after removing
neoplastic lesions is far larger than taking simple superficial biopsies as is
the case in this study. Biopsies are only taken from the mucosa and will not
reach the deeper layers of the colon as is for example the case when removing
polyps with diathermy. Furthermore, also colonoscopies without taking biopsies
or neoplastic lesion removal give a risk of perforation that is comparable to
colonoscopies with taking biopsies (0.6 per 1000 procedures). In this procedure
colonoscopy is part of regular patient care and only taking the biopsies is
part of the study. Therefore the additional risk of taking biopsies for this
study is estimated to be very small.