PROGNOSTIC SIGNIFICANCE OF DOUBLE STRAND BREAK REPAIR GENE EXPRESSION IN SPORADIC COLORECTAL CANCER

Introduction: Beyond characterization of mismatch repair deficiency in colorectal cancer (CRC), the status of other DNA repair pathways is not investigated in standard clinical practice. However, it has been reported that most of colorectal tumors harbor deficiencies in homologous recombination repair (HRR) due to mutations in genes other than BRCA1/2, which configures the so called BRCA-ness signature. Therefore, the examination of HRR profile could provide new insights on prognosis and expand the therapeutic options for CRC. Aim: to evaluate the association of expression of key components of HRR with prognostic aspects of patients with colorectal tumors undergoing surgery. Methodology: Tumor specimens and matched healthy mucosal tissues from 48 patients with CRC were assessed for gene expression of the HRR genes by qRT-PCR. Seventy-nine pre-treatment CRC patients who underwent surgery were prospectively included. 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 independent prognostic value. Results: RAD50 and RBBP8 presented a mean -2.19 and -1.97-fold gene expression reduction (p<0.05), respectively; MRE11A and PALB2 exhibited a mean 2.26 and 2.07Dfold induction, respectively (p<0.05). NBN over expression and low expression of PALB2 were confirmed as independent predictors of overall survival (OS) following multivariate analysis (NBN – HR: 10.505, IC 95% [2.197 – 53.232], p=0.005; PALB2 – HR: 14.451, IC 95% [1.205 – 166.087], p= 0.032). High LMR and NLR were associated with poorly differentiated colorectal tumors and pT III-IV. Low LMR (<3) was associated with reduction of PALB2 gene expression. Conclusions: Our results suggest that NBN and PALB2 gene expression are potential candidates to evaluate colorectal cancer prognosis. Further studies must investigate the role of this bio markers as a treatment target to improve outcomes of CRC.