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Background: Homologous recombination repair (HR) is the most accurate repair pathway for double-strand breaks and replication fork disruption that is capable of faithfully restoring the original nucleotide sequence of the broken DNA. The deficiency of this mechanism is a frequent event in tumorigenesis. Therapies that exploit defects in HR have been explored essentially in breast, ovarian, pancreatic, and prostate cancers, but poorly in colorectal cancers (CRC), although CRC ranks second in mortality worldwide. Methods: Tumor specimens and matched healthy tissues from 63 patients with CRC were assessed for gene expression of key HR components and mismatch repair (MMR) status, which correlated with clinicopathological features, progression-free survival, and overall survival (OS). Results: Enhanced expression of MRE11 homolog (MRE11A), the gene encoding a key molecular actor for resection, is significantly overexpressed in CRC, is associated with the occurrence of primary tumors, particularly T3-T4, and is found in more than 90% of the right-side of CRC, the location with the worst prognosis. Importantly, we also found that high MRE11A transcript abundance is associated with 16.7 months shorter OS and a 3.5 higher risk of death. Conclusion: Monitoring of MRE11 expression could be used both as a predictor of outcome and as a marker to select CRC patients for treatments thus far adapted for HR-deficient cancers.

Abstract 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

Objective to evaluate the prognostic value of base excision repair proteins in sporadic colorectal cancer. Methods Pre-treatment tumor samples from 72 patients with sporadic colorectal adenocarcinoma were assessed for APC, MPG, Polβ, XRCC1 and Fen1 expression by immunohistochemistry. The associations of molecular data were analyzed in relation to clinical features and TNM staging as a prognosis predictor and disease-free survival. Results Higher levels of MPG, Polβ and XRCC1, but not Fen1, were associated with unfavorable pathological outcomes, such as poor cellular differentiation, advanced TNM stages, presence of lymphatic and perineural invasions and metastatic lymph nodes. MPG and Polβ overexpression were associated with right-sided CRC. However, only MPG high expression is associated with shorter disease-free survival in CRC patients. Conclusions Our results suggest that increased expression of MPG, Polβ and XRCC1 are more likely to evolve to poor pathological outcomes, but only the elevated expression of MPG protein predicts recurrence. The BER proteins appear to be suitable candidates to refine the TNM current staging of colorectal cancer.

// Natalia M. Leguisamo 1 , Helena C. Gloria 1 , Antonio N. Kalil 1, 2 , Talita V. Martins 2 , Daniel B. Azambuja 1, 2 , Lisiane B. Meira 3, * and Jenifer Saffi 1, * 1 Genetic Toxicology, Universidade Federal de Ciencias da Saude de Porto Alegre (UFCSPA), Porto Alegre, Rio Grande do Sul, Brazil 2 Oncology and Colorectal Surgery, Santa Casa de Misericordia de Porto Alegre (ISCMPA), Porto Alegre, Rio Grande do Sul, Brazil 3 Department of Clinical and Experimental Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, United Kingdom * These authors share senior authorship Correspondence to: Natalia M. Leguisamo, email: nmleguisamo@gmail.com Keywords: colorectal cancer, base excision repair, prognosis, energy metabolism, temozolomide Received: February 29, 2016 Accepted: November 30, 2016 Published: January 31, 2017 ABSTRACT Colorectal cancer (CRC) is prevalent worldwide, and treatment often involves surgery and genotoxic chemotherapy. DNA repair mechanisms, such as base excision repair (BER) and mismatch repair (MMR), may not only influence tumour characteristics and prognosis but also dictate chemotherapy response. Defective MMR contributes to chemoresistance in colorectal cancer. Moreover, BER affects cellular survival by repairing genotoxic base damage in a process that itself can disrupt metabolism. In this study, we characterized BER and MMR gene expression in colorectal tumours and the association between this repair profile with patients’ clinical and pathological features. In addition, we exploited the possible mechanisms underlying the association between altered DNA repair, metabolism and response to chemotherapy. Seventy pairs of sporadic colorectal tumour samples and adjacent non-tumour mucosal specimens were assessed for BER and MMR gene and protein expression and their association with pathological and clinical features. MMR-deficient colon cancer cells (HCT116) transiently overexpressing MPG or XRCC1 were treated with 5-FU or TMZ and evaluated for viability and metabolic intermediate levels. Increase in BER gene and protein expression is associated with more aggressive tumour features and poor pathological outcomes in CRC. However, tumours with reduced MMR gene expression also displayed low MPG , OGG1 and PARP1 expression. Imbalancing BER by overexpression of MPG , but not XRCC1 , sensitises MMR-deficient colon cancer cells to 5-FU and TMZ and leads to ATP depletion and lactate accumulation. MPG overexpression alters DNA repair and metabolism and is a potential strategy to overcome 5-FU chemotherapeutic resistance in MMR-deficient CRC.