Data from the Global Cancer Observatory (GLOBOCAN) shows that colorectal cancer is the third most lethal cancer in the world. Millions of new cases are diagnosed each year, with a trend that is steadily increasing—and this growth is fastest in countries where the “western diet” is prevalent. Lifestyle factors seem to contribute to some extent. Researchers are scrambling to make sense of exactly how.
In fact, a subtype of colorectal cancer is known as sporadic colorectal cancer (CRC) occurs in individuals with no known genetic risk factors, but rather as a result of some sort of interplay between the individual and their environment. It’s possible that a person’s epigenetics can be altered by certain environmental stressors, which could then lead to developing CRC but details about the mechanisms involved need to be elucidated.
Oncomix forms to study colorectal cancer
in April 2016, a research group known as “Oncomix” emerged to study colon cancer, led by Professor Philippe Sansonetti, chair of Microbiology and Infectious Diseases at the Collège de France. Oncomix is comprised of professionals including members in gastroenterology from Henri-Mondor AP-HP Hospital, and University Paris-Est Créteil, Inserm, and the Institut Pasteur Molecular Microbial Pathogenesis Unit (U1202).
Oncomix examined the role that the gut microbiota—or the environment of microorganisms known too inhabit the gut and even contribute in part to digestive processes—plays in the development of CRC. Researchers focused on mice for their preliminary studies, then shifted their analyses to human subjects.
Mice showed epigenetic changes when exposed to CRC microbiota
In the first part of their study, researchers transplanted fecal samples from patients with a healthy colon, or from CRC patients— to mice and monitored for seven or 14 weeks. They monitored changes in the crypt foci, the microbiota of the lumen, and in the DNA methylation patterns.
DNA methylation is an epigenetic modification that involves the addition of a methyl group to the DNA. This addition doesn’t change the DNA sequence itself, but it can alter gene expression. It plays a major role in human development, aging, and different cancers—making it an important mechanism to explore.
In the mice given fecal samples from the CRC patients, DNA examination revealed major changes in methylation levels. These mice showed much higher numbers of methylated genes, particularly in the colonic mucosa (or, the surface tissues of the colon). These genes included several promoters, such as SFRP1,2,3, PENK, NPY, ALX4, SEPT9, and WIF1; all of which were differentially hypermethylated in the CRC patients but not in the healthy patients.
Blood tests in humans showed hypermethylation in CRC patients
There were actually two studies done to try and extend the mouse findings into humans, and both of them involved examining epigenetic changes to specific genes in CRC patients versus healthy adults.
In the first study of 266 individuals, methylation levels were examined and three specific genes—Wif1, PENK, and NPY—were found to be hypermethylated and closely linked to imbalances in the gut microbiota (dysbiosis).
Researchers then dug into statistical analysis through the validation study of one thousand individuals, split between normal adults and CRC patients. The cumulative methylation index (CMI) was higher in individuals with CRC, consistent with the hypermethylation results found earlier, confirming the relationship between high CMI and dysbiosis in humans.
In this way, environmental stressors seem to trigger epigenetic changes in these cells via hypermethylation of genes, including some promoter, where the make-up of the gut dysbiota was heavily altered.
The development of a blood test for diagnosing CRC or even as a prognostic indicator would be a huge step forward. As a less invasive method than existing colonoscopies, blood tests are less risky, less time-consuming, and less expensive. Because it would be easier and more affordable, such a blood test would be expected to open up access to testing for CRC; this could result in more frequent early detection and a higher incidence of positive patient outcomes.
Researchers are actively decoding the pathways that contribute to the incidence of colorectal cancer in hopes of ultimately preventing it from occurring. Given the scale at which it is being diagnosed, even curbing the number of new annual cases would have a huge positive impact.
Source: Sansonetti P et al.(2019) Colorectal cancer-associated microbiota contributes to oncogenic epigenetic signatures. PNAS, 116 (48).
Reference: Institut Pasteur. “Gut Microbiota Imbalance Promotes the Onset of Colorectal Cancer” Institut Pasteur Press Releases. 12 Nov 2019. Web.