Association of DNA Repair Modulation and Aggressiveness in Colorectal Cancer Liver Metastasis

Introduction: Curative effectiveness of colorectal cancer liver metastases (CRCLM) is limited by poor understanding of the molecular pathways that drive metastases and recurrence. As previously reported by our group, in primary colorectal cancer (CRC), DNA repair pathways imbalance reflects tumor aggressiveness. However, the role of this system in CRCLM development is not clear. The aim of the present study was to characterize the main DNA repair components in resected CRCLM. Methods: Immunohistochemistry for MLH1 (mismatch repair - MMR); OGG1 and MPG (base excision repair-BER) and Ku80 (non-homologous end-joining - NHEJ) was performed on CRCLM and healthy surrounding liver specimens obtained from patients who underwent to liver resection surgery. The association between staining and the clinicopathological data was examined. Results: Our preliminary data on eleven consecutive CRCLM patients showed negative or reduced MLH1 expression in 27% of the cases, indicating the presence of microsatellite instability. MMR pathway functionality in liver metastases is associated with lower levels of CEA. While the reduction of Ku80 protein levels in neoplastic specimens is associated with unilateral occurrences of CLCLM, increases in Ku80 and MPG contents are associated with greater number of metastatic hepatic lesions. Conclusion: The association between the overexpression of BER glycosylase MPG and Ku80 NHEJ key-component with features of tumor aggressiveness suggest a new field of study for the comprehension of the molecular development of CRCLM.