Colorectal cancer, intestinal carcinoma, colon cancer, bowel neoplasia, 3D illustration
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Researchers at Georgetown University’s Lombardi Comprehensive Cancer Center have shown that the microbiome within tumors from patients with early-onset colorectal cancer (CRC) differs significantly from that of patients with late-onset disease.

The findings, which will be presented at the American Society of Clinical Oncology 2023 annual meeting in Chicago in June, may help explain why the incidence of CRC in individuals under 45 years of age has risen dramatically.

“We’re trying to help explain why younger adults (under 45) are getting colorectal cancer since the mid-1990s,” presenting author Benjamin Adam Weinberg, an associate professor of medicine at Georgetown Lombardi told Inside Precision Medicine. “We think there was some exposure or cohort effect in the 1970s or 1980s that led to this phenomenon which is ongoing and mostly causes left-sided colon and rectal cancers.”

Increasing rates of obesity and diabetes may partially explain the epidemiological shift toward younger patients, but many individuals with early-onset CRC are neither obese nor diabetic.

“Younger-onset disease tends to be more aggressive biologically, and, in patients with advanced disease, whatever survival benefit from being younger is essentially counterbalanced by this more aggressive biology,” said Weinberg. “If you examine the tumor genetics in younger left-sided colon and rectal cancers versus older left-sided colon and rectal cancers, there are not significant differences to account for this rise in young-onset colorectal cancer.

“Thus, we think microbiome, specifically the microbiome within the tumor itself, may be playing a role.”

Indeed, certain bacteria, particularly Fusobacterium nucleatum, have already been implicated in colorectal carcinogenesis and may also play a role in the tumor spreading to other parts of the body.

Fusobacterium nucleatum promotes CRC by suppressing the immune response within the tumor microenvironment, activating the β-catenin pathway, and causing resistance to chemotherapy.

Weinberg and team therefore hypothesized that F. nucleatum would be more common in younger than older patients with colorectal cancer.

To investigate, they used 16S ribosomal gene sequencing to compare the frequency of F. nucleatum and other bacterial and fungal DNA in primary and metastatic tumors from 36 patients with early-onset CRC (median age 38 years) and 27 patients with late-onset CRC patients (median age 72 years).

The team identified 917 unique bacterial and fungal species overall but contrary to their hypothesis, the rates of F. nucleatum were almost the same between the patients with early-onset CRC and those with late-onset CRC, at 30.6% and 29.6%, respectively.

There were, however, significant differences between the two groups in several other species detected. Specifically, Cladosporium sp. was significantly more common in early-onset CRC than in late-onset CRC (30.6 vs 11.0%,), whereas Pseudomonas luteola (2.8 vs 22.2%), Ralstonia sp. (22.2 vs 48.1%), and Moraxella osloensis (19.4 vs. 44.4%) were significantly less common in early-onset disease.

Clostridium perfringens, Escherichia coli, Leptotrichia hofstadii, Mycosphaerella sp, Neodevriesia modesta, Penicillium sp., and Leptosphaeria sp. occurred exclusively in late-onset CRC, each at a rate of 11.1%.

Of note, there was no significant difference in microbiome diversity in early- vs late-onset CRC, with a median of 43 and 45 organisms detected per patient, respectively.

There was also no significant difference in median overall survival between the patients with early- versus late-onset CRC (75.5 vs 60.0 months) and no significant difference between those with (n=17) and without (n=46) F. nucleatum present in their tumors (75.5 vs 60.0 months).

Weinberg stressed that the findings are hypothesis-generating and now need to be validated in larger studies.

In addition, his team hopes to carry out “more studies on flash-frozen treatment-naïve samples which mitigate risk of contaminating tumor samples with other bacteria and fungi.”

The group is also interested in looking at the circulating microbiome to see what bacterial DNA can be detected in blood samples and how it relates to the gut and intratumoral microbiomes.

“Ideally, we would be able to [use a blood-based test to] identify patients with a poor gut microbiome which may increase their susceptibility to develop colorectal cancer, and maybe these individuals need colonoscopic screening prior to age 45,” Weinberg remarked.

He added: “Finally, specific bacteria may serve as novel therapeutic targets, so more needs to be understood regarding the roles of specific bacteria in the cancer growth and metastatic processes.”

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