The role of double-strand break repair, translesion synthesis, and interstrand crosslinks in colorectal cancer progression-clinicopathological data and survival.

Gustavo A Laporte,Helena De Castro E Gloria,Natália M Leguisamo,Antonio N Kalil,Jenifer Saffi,Daniel B Azambuja

doi:10.1002/jso.25737

Abstract

DNA repair is a new and important pathway that explains colorectal carcinogenesis. This study will evaluate the prognostic value of molecular modulation of double-strand break repair (XRCC2 and XRCC5); DNA damage tolerance/translesion synthesis (POLH, POLK, and POLQ), and interstrand crosslink repair (DCLRE1A) in sporadic colorectal cancer (CRC). Tumor specimens and matched healthy mucosal tissues from 47 patients with CRC who underwent surgery were assessed for gene expression of XRCC2, XRCC5, POLH, POLK, POLQ, and DCLRE1A; protein expression of Polk, Ku80, p53, Ki67, and mismatch repair MLH1 and MSH2 components; CpG island promoter methylation of XRCC5, POLH, POLK, POLQ, and DCLRE1A was performed. Neoplastic tissues exhibited induction of POLK (P < .001) and DCLRE1A (P < .001) expression and low expression of POLH (P < .001) and POLQ (P < .001) in comparison to healthy paired mucosa. Low expression of POLH was associated with mucinous histology and T1-T2 tumors (P = .038); low tumor expression of POLK was associated with distant metastases (P = .042). CRC harboring POLK promoter methylation exhibited better disease-free survival (DFS) (P = .005). This study demonstrated that low expression or unmethylated POLH and POLK were related to worse biological behavior tumors. However, POLK methylation was associated with better DFS. POLK and POLH are potential prognostic biomarkers in CRC.

Highlights

Colorectal cancer (CRC) is considered the third major cause of cancer‐related death worldwide [1,2,3]
This study mainly demonstrated that low expression or unmethylated POLH and POLK were related to worse biological behavior tumors
POLK methylated was associated with better disease free survival (DFS)

Summary

Introduction

Colorectal cancer (CRC) is considered the third major cause of cancer‐related death worldwide [1,2,3]. Survival rates and therapeutic decisions for CRC patients essentially depend on pathology-related staging following the tumour-node-metastasis (TNM) classification [4]. Despite modifications to improve prognostic staging, this algorithm still fails to predict recurrence and survival after resection for stage II and III CRC patients, resulting in heterogeneous and controversial oncological outcomes [5]. In the pursuit for eliminating TNM inconsistencies, CRC molecular complexity and its heterogeneous clinical presentations have been leading to the research of novel prognostic and predictive biomarkers, including DNA repair components. CRC patients which harbour DNA mismatch repair (MMR) system defects and, microsatellite instability (MSI) [6], have better stage-adjusted survival and reduced likelihood of metastasis when compared to microsatellite stable (MSS) tumors [7,8].

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