IDENTIFICATION OF DNA REPAIR SYSTEMS IMBALANCES AND ITS ASSOCIATION WITH CLINICAL ASPECTS OF COLORECTAL LIVER METASTASIS

Background:Approximately 50% of patients with colorectal cancer will develop distant metastasis, and liver is the main site to harbor neoplastic disease spread. Additionally, colorectal liver metastases (CLM) are the main cause of death in these patients. DNA repair systems imbalances may influence tumor aggressiveness and response to chemotherapy. However, the role of these pathways on colorectal metastatic progression in the liver has not yet been elucidated. Thus, this study aimed to identify alterations in the key components of two DNA repair pathways, named base excision (BER) and double breaks (DSBR) repair and its association with clinicopathological features of tumor aggressiveness in CLM patients. Patients and Methods: We prospectively evaluated 50 patients who underwent hepatectomy due to CLM. Fresh and FFPE matched neoplastic and healthy liver tissues were evaluated for gene expression of OGG1, POLB, PARP1, XRCC1, RAD51, BRCA1 and Ku80 (qRT-PCR). Gene expression presented as Fold Change (FC) Log2 (neoplastic/healthy tissue). Molecular data was associated with clinicopathological variables. Univariate and multivariate analyzes were performed considering P < 0.05. Results: BER pathway presented imbalance due to reduction of PARP1 expression (FC = - 3.10; P < 0.001) and XRCC1 overexpression (FC = 2.47; P < 0.05). OGG1 and POLB did not present alterations. As regards the DSBR pathway, RAD51 and BRCA1 presented reverse modulation (FC = 4.02, P < 0.001 and FC = - 4.73, P < 0.001), while Ku80 presented a reduction in their levels (FC = - 2, 80, P < 0.05). Higher levels of XRCC1 and OGG1 were associated with more advanced primary stage and metachronous metastasis, left-sided colorectal tumors and shorter interval until metastatic progression. Lower levels of Ku80 and BRCA1 were associated with occurrence of smaller metastatic lesions, but higher number of involved segments, respectively. Conclusions: The results suggest a profile of increased tumor aggressiveness associated to the reduction of signaling and processing of simple and double strand breaks. BER and DSBR imbalances opens a new field for the study of possible biomarkers in CLM subtypes identification, with potential to improve therapeutic decision making and clinical outcomes.

 

MissingLinkText

No conflict of interest has been declared by the author(s).

Publication History

Article published online:
23 October 2019