PROGNOSTIC VALUE OF BASE EXCISION REPAIR PATHWAY IN PATIENTS WITH RESECTABLE COLORECTAL LIVER METASTASES

Introduction: Colorectal liver metastases (CRCLM) remains the major cause of death of colorectal cancer (CRC) patients. Inappropriate repair of DNA damage promotes genomic instability, increase of mutational burden and upregulation of PD-1/PD-L1 axis. Mismatch repair deficiency (dMMR) is a validated DNA repair-based biomarker for predicting response to immunotherapy for metastatic CRC. Since only 5% of CRCLM patients present dMMR, identification of deficiencies in other DNA repair pathways, such as base excision repair (BER), might facilitate the identification of patients who would possibly benefit from immunotherapy irrespective of dMMR. Aim: to evaluate the association of expression of key components of BER with prognostic aspects of patients with liver metastases from colorectal tumors undergoing surgery. Methodology: Fifty patients were prospectively included. CRCLM and adjacent non involved liver specimens from 32 patients who underwent hepatectomy were assessed for gene expression of the key BER genes (OGG1, POLB, PARP1 and XRCC1) by qRT-PCR and PARP1 and PD-1 protein expression by immunohistochemistry. Molecular and clinicopathological data, including inflammatory-based scores (neutrophil/lymphocyte, lymphocyte/monocyte and platelet/lymphocyte ratios – NLR, LMR and PLR, respectively), were investigated for associations and prognostic value. Results: Reduction of OGG1 and POLB mRNA levels in neoplastic tissues were associated with synchronous CRCLM and R1-R2 surgical margins, respectively. Overexpression of PARP1 was associated with smaller liver metastasis and increased LMR ratio, and XRCC1 overexpression was associated with lower CEA levels at CRC diagnosis and increased PLR. Moreover, we demonstrated that CRCLM tissues exhibiting lower immunoreactivity of PARP1 were associated with presence of perineural invasion in colorectal tumors and increased NLR. In counterpart, high PARP1 expression was associated with positive PD-1 expression in CRCLM. Survival analyses did not confirm the independent prognostic role of BER components. Conclusions: BER pathway is imbalanced in CRCLM. PARP1 upregulation was associated with positive PD-1 and clinical features of poor prognosis in CRCLM, which may suggest a novel role for PARP1 in CRCLM aggressiveness by immune system activation and modulation of tumor development.