The aim of the study was the identification of a pharmacogenetic profile predictive of the tumor regression grade (TRG), considered as tumor response parameter, after neo-adjuvant treatment in rectal cancer patients. A total of 238 rectal cancer patients treated in a neo-adjuvant setting by a fluoropyrimidines-based chemo-radiotherapy (RT) were genotyped for 25 genetic polymorphisms in 16 genes relevant for treatment-associated pathways. Two polymorphisms were associated with TRG in a multivariate analysis: hOGG1-1245CG, which can affect radiosensitivity and MTHFR-677CT, which is involved in fluoropyrimidines action. Patients bearing at least one variant allele had a lower chance to get TRG2 (OR0.46 95% CI 0.23-0.90, P0.024; and OR0.48 95% CI 0.24-0.96, P0.034; respectively). An association trend was observed for ABCB1-3435CT, which is responsible for the multi-drug resistance (odds ratio (OR)1.96, 95% confidence interval (CI) 0.98-3.95, P0.057). Exploratory classification and regression tree (CART) analysis highlighted high-order gene-gene and gene-environment interactions and a genetic signature associated with differential response, with hOGG1-1245CG as the most predictive factor. Other significant variables were: ABCB1-3435CT, MTHFR-677CT, ERCC1-8092CA, ABCC2-1249GA, XRCC1-28152GA, XRCC3-4541AG and patients gender. On the basis of CART results, patients were categorized into three groups according to tumor response probability: intermediate and high profiles had a higher probability to get TRG2 as compared with low profiles (OR4.12 95% CI 1.46-11.65, P0.001 and OR12.44, 95% CI 5.52-28.04, P0.0001, respectively). This study evidences a major role of hOGG1-1245CG and MTHFR-677CT polymorphisms in the tumor response of rectal cancer patients treated with chemo-RT in neo-adjuvant setting, and shows the relevance of gene-gene and gene-environment interactions for complex phenotypes as tumor response.
ASJC Scopus subject areas
- Molecular Medicine