Gut microbiome may contribute to pathogenesis of MSI colon cancers, study finds

Researchers at the Rutgers Cancer Institute of New Jersey, the only National Cancer Institute – Designated Comprehensive Cancer Center in New Jersey, conducted a collaborative study to examine patterns of oncogenic drug fusions in colon cancer specimens, including microsatellite tumors stable and unstable (MSI). Subhajyoti De, PhD, researcher at Rutgers Cancer Institute and Shridar Ganesan, MD, PhD, chief of molecular oncology, associate director for translational research, and holder of the Omar Boraie chair in genomic science at Rutgers Cancer Institute, both members of Rutgers Robert Wood Johnson Medical School faculty, are senior authors of the work and share more about the results published in the online version of JCO Precision Oncology (DOI: 10.1200/PO.21.00477).

Why is it important to explore this topic?

A subset of colorectal carcinoma (CRC) arises as part of an underlying defect in mismatch repair leading to microsatellite instability (MSI), a phenotype defined by variation in the length of microsatellite repeats. MSI colon cancers are highly susceptible to immune checkpoint blockade, and advanced occurrences of this disease are now routinely treated with such agents approved for this indication. Unfortunately, only about half of patients with CRC MSI benefit from these agents, creating an unmet need for other treatment approaches for these cancers. It is possible that combination therapy targeting oncogenic driver fusion genes and immune checkpoint blockade may lead to improved long-term outcomes in kinase fusion positive CRC MSI.

Describe the work and tell us what the team discovered.

This collaborative project examined patterns of oncogenic drug fusions in 32,218 colon cancer samples, including stable and unstable microsatellite (MSI) tumors. Dr. Russell Madison of Foundation Medicine and Dr. Xiaoju Hu of Dr. De’s lab are co-first authors of this work. Their analysis indicated that MSI CRCs are enriched for specific gene fusions, particularly those involving NTRK1 and NTRK3, as well as RET, ALK, and BRAF. Interestingly, this enrichment of oncogenic fusions in MSI cancer appears to be restricted to CRC, and not observed in MSI endometrial cancer or other MSI cancers in general, suggesting that the enrichment of specific gene fusions in CRC MSI can be both due to the MSI phenotype and a tissue specific effect of origin. Detailed analysis of breakpoints in MSI-associated kinase fusions supports a model in which ineffective repair and/or processing of microbiome-induced bundled 8-oxo-G damage in the MSI CRC contributes to the increased incidence of specific oncogenic fusions.

What are the implications of these findings?

This study provides clues as to why colon cancer harboring MSI is enriched for specific oncogenic kinase fusions, which are rare in other cancers deficient in mismatch repair. The team reports that repair of 8-oxo-G adducts, which occur in the gut as a byproduct of microbial metabolism, is impaired in mismatch repair defective tumors, promoting mutagenesis and DNA breaks. DNA, probably causing these oncogenic fusions. Thus, the combination of the DNA repair defect present in these cancers and the presence of microbiome-induced DNA damage may lead to an increased incidence of gene fusion in MSI colon cancers. These observations may help rationally prioritize oncogenic driver fusion genes for combination therapy with immune checkpoint blockade, which may lead to better outcomes in a subset of CRC patients. These data also suggest that the gut microbiome may contribute to the pathogenesis of a subset of MSI colon cancers.


Journal reference:

Madison, RW, et al. (2022) Clustered 8-oxo-guanine mutations and oncogenic gene fusions in unstable microsatellite colorectal cancer. JCO Precision Oncology.

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