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Colorectal Cancer Microbiomes May Differ With Mismatch Repair Status

NEW YORK (GenomeWeb) – The microbial communities found in and around colorectal cancer (CRC) tumors may differ depending on the DNA mismatch repair (MMR) status of the CRC involved, new research suggests.

As they reported online yesterday in Genome Medicine, researchers from the Mayo Clinic, Rochester and elsewhere used 16S ribosomal RNA gene sequencing to assess tumor and matched normal colon tissue and mucosa samples from dozens of individuals with CRC, bolstering the microbiome data with metabolic modeling based on metabolomic measurements for a subset of participants.

A few microbial species appeared to be particularly prevalent in samples from individuals with mutation-rich, MMR-deficient (dMMR) CRCs relative to the normal samples or to the "proficient" MMR (pMMR) tumors, the team noted. For example, the MMR-deficient tumors tended to have enhanced levels of Bacteroides fragilis, a species previously implicated in inflammation and CRC risk, and Fusobacterium nucleatum, a hydrogen sulfide-producing bug, along with a corresponding jump in hydrogen sulfide-associated amino acids.

"Integrating tumor biology and microbial ecology highlighted distinct microbial, metabolic, and ecological properties unique to dMMR and pMMR CRC," senior author Nicholas Chia, a microbiome and surgery researcher at the Mayo Clinic, and his colleagues wrote, adding that their approach "could critically improve our ability to define, predict, prevent, and treat colorectal cancers."

The composition and functional wherewithal of microbial communities in the gut have been associated with CRC tumorigenesis, tumors, and metastases in the past, the team explained, though specific microbiome features involved tend to vary from one study to the next.

For their new analysis, the researchers focused on potential microbiome differences aligned with the MMR status of CRC tumors from 83 individuals with available tumor and normal, tumor-adjacent tissue and/or mucosa samples obtained during bowel resection surgery.

When they gauged MMR status based on expression of the MLH1, MSH2, MSH6, and PMS2 MMR, assessed by RNA sequencing from formalin-fixed, paraffin-embedded tumor samples, they identified 25 cases that were MMR deficient and 58 pMMR cases.

From there, the team did Illumina MiSeq 16S amplicon sequencing on paired tumor-normal samples to get a look at the microbial community members in patient samples. The researchers also used real-time PCR to test for the presence of a characteristic toxin produced by B. fragilis and quantified amino acid and short-chain fatty acid levels in samples from 50 cases using ultra performance liquid chromatography mass spectrometry-based targeted metabolomics.

Using these data, the researchers saw a boost in specific bacterial species in the CRC with DNA mismatch repair problems — results they replicated in dMMR or microsatellite instable cases from an independent set of matched tumor-normal samples from 44 individuals with CRC.

The dMMR tumors tended to have higher levels of Coprococcus comes and B. massiliensis compared to the pMMR samples, while Fusobacterium and B. fragilis were over-represented in dMMR tumors relative to normal tissue or mucosa.

On the other hand, the team found that MMR-capable tumors were more apt to contain Faecalibacterium prausnitzii and Blautia species than the dMMR tumors, though both dMMR and pMMR tumors had levels of Dorea longicatena bacteria that exceeded those in matched normal samples.

"Our work demonstrates distinct microbial, metabolic, and ecological attributes of dMMR and pMMR microbial communities," the authors wrote, "serving to further emphasize the importance of considering tumor biology and microbial interactions in studies of the CRC microbiome."

The current findings represent a descriptive look at the microbiome differences in MMR, pMMR, and matched normal samples, the authors cautioned, noting that "[w]hile we make speculations based on these [descriptive] data, future prospective and mechanistic studies are needed to test these ideas."

Even so, they noted that the study "demonstrates the importance and value in considering tumor biology (MMR status) and ecological interactions when evaluating microbial community data."