Abstract
Background: DNA mismatch repair (MMR) system maintains genomic stability and mediates cellular response to DNA damage. Recent studies have shown that a subset of MMR deficient pancreatic ductal adenocarcinoma (PDAC) may represent promising candidates for immunotherapy. Inflammation can promote PDAC development and progression, with a key role played by cytokines, such as IL-6, and cyclooxygenase-2 (COX-2). Studies on other gastrointestinal malignancies have demonstrated a link between IL-6 and loss of MMR expression. In this study we analyzed the correlation between MMR protein expression and inflammation markers in PDAC. Methods: Tissue samples from 91 resected PDAC patientswere subjected to immunohistochemical staining to assess the expression of MLH1, MSH2 and MSH6. Stromal and tumoral IL-6 levels and COX-2 expression were also assessed with immunohistochemistry. Expression of MMR proteins was correlated with IL-6 and COX-2 expression by chi-square test. Results: At immunohistochemistry analysis, 42.2% of samples were negative for MLH1 expression, while 27.7% were negative for MSH2 and 34.4% for MSH6. Nineteen patients (20.9%) presented loss of at least two MMR proteins. Stromal and tumoral IL-6 was expressed in 55.6% and 44.4% of samples, respectively, while COX-2 was found in 62.5% of samples. MMR protein expression was not related to clinical characteristics, as pathological stage or grading, or to clinical outcome in terms of overall survival (OS). MMR deficiency, defined as loss of at least one of the three MMR protein analysed, significantly correlated with expression of stromal IL-6 (p= 0.005). Moreover, we showed a significant correlation between MMR deficiency and high expression of both inflammation markers (p= 0.0009) with 69.5% of MMR deficient tumors with expression of both IL-6 and COX-2. Conclusions: Our results suggest that MMR deficiency and inflammation are correlated in human PDAC pathogenesis, confirming what observed in other gastrointestinal tumors. These results give new insights on the role of inflammation in PDAC and should be considered in the selection of patients for future development of immunotherapies in PDAC.
Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
