Abstract IA4: The role of inflammation and DNA mismatch repair in colorectal cancer
Authors: Carethers John M. 
Published: December 2017

Anti-inflammatory drugs, such as aspirin, have been identified as agents that can serve a primary preventative approach towards lessening the burden of colorectal cancer (CRC), as well as be effective secondary prevention for CRC recurrence. Genetic and epigenetic events that drive the pathogenesis of CRC influences a relationship with the immune system that modifies cancer behavior and patient prognosis, as well as the effectiveness of anti-inflammatory drugs and other agents for chemoprevention. Approximately 15% of sporadic CRCs manifest defective DNA mismatch repair (MMR) function due to epigenetic inactivation of the MMR gene MLH1, allowing cancer cells to accumulate hundreds of somatic frameshift mutations in genes that contain microsatellite sequences. Most of the coding microsatellite frameshift mutations are translated into novel truncated proteins, which act as neo-antigens to the patient's immune system, with the patient self-immunizing against the tumor. This defective MMR-driven inflammatory response slows the ability of the CRC to advance and metastasize, and patients present at an earlier stage and survive longer compared to CRC patients with competent MMR tumors. MMR-defective CRCs acquire PD-1 expression, making the tumor more susceptible to immune checkpoint blockade. However, these patients show muted response to adjuvant 5-fluorouracil (5-FU) therapy. There is evidence that aspirin is chemopreventive in Lynch syndrome, a familial form of MMR deficiency, but needs to be studied further. Additionally, approximately 50% of all CRCs manifest dysfunction of the MMR protein MSH3 as a consequence of inflammation and release of the pro-inflammatory cytokine IL-6 from intimately-located immune cells. The isolated MSH3 dysfunction allows cancer cells to accumulate non-mononucleotide microsatellite frameshift mutations that are likely not very immunogenic, as well as DNA double strand breaks as a consequence of loss of MSH3s contribution to homologous recombination repair. These CRC patients are more apt to be advanced stage and possess metastases, demonstrate poor survival, and more common among African American patients. Isolated loss of MSH3 function does not hinder a patient's response to 5-FU, and the effectiveness of immune checkpoint blockade and anti-inflammatory agents has not been tested to date. Specific chromosome breakage points such as at chromosome 9p24.2 are enriched in liver metastases from CRCs with MSH3 dysfunction and modify patient outcome by increasing survival over patients with MSH3 dysfunction alone. Overall, the MMR status of the CRC can inform approach to patient care, and the outcome difference depends on if the MMR defect drives an immune response, or if acquired inflammation causes disruption of MMR via MSH3 cellular mis-localization.

Citation Format: John M. Carethers. The role of inflammation and DNA mismatch repair in colorectal cancer [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr IA4.