Aim: To evaluate the prognostic value of molecular modulation of double strand break (DSBR) - XRCC2 and XRCC5 - core components; DNA damage tolerance/translesion synthesis (DDT/TLS) - POLH, POLK and POLQ – and, finally, of interstrand crosslink repair (ICLR) -DCLRE1A – pathways in sporadic colorectal cancer (CRC) progression. Method: Tumour specimens and matched health mucosal tissues from 47 patients with CRC who underwent surgery were assessed for gene expression of XRCC2, XRCC5, POLH, POLK, POLQ and DCLRE1A by qRT-PCR; protein expression of Polk, Ku80, p53, Ki67 and mismatch repair MLH1 and MSH2 components were assessed by immunohistochemistry (IHC); CpG island promoter methylation of XRCC5, POLH, POLK, POLQ and DCLRE1A was performed. Uni and multivariate analyses were employed to determine associations with clinicopathological features and prognostic value of molecular data. Results: Neoplastic tissues exhibited induction of POLK (p<0.001) and DCLRE1A (p<0.001) expression and low expression of POLH (p<0.001) and POLQ (p<0.001) in comparison to healthy paired mucosa. Low expression of POLH was associated to mucinous histology and T1-T2 tumors (p=0.038); low tumour expression of POLK was associated to distant metastases (p=0.042). POLK promoter methylation was associated to early stages CRC (p=0.011) and POLH promoter methylation to high grade tumors (p=0.023). CRC harbouring POLK promoter methylation exhibited better disease free survival (DFS) (p=0.005). Conclusion: This study mainly demonstrated that low expression or unmethylated POLH and POLK were related to worse biological behavior tumors. However, POLK methylated was associated with better DFS. POLK and POLH are potential prognostic biomarkers in CRC.

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