Analysis of Variants in Cytochrome P450 Superfamily Genes as Predictive Markers for Neoadjuvant Chemoradiotherapy in Rectal Cancer

Abstract

Background: Patients with locally advanced rectal cancer (LARC) often receive neoadjuvant chemoradiotherapy (nCRT) based on 5-fluorouracil (5-FU). Cytochrome P450 (CYP) enzymes, involved in drug metabolism and carcinogenesis, may influence response to therapy. Variability in CYP gene expression makes them promising biomarkers for predicting treatment outcomes in rectal cancer. Material and methods: Genomic DNA from 38 LARC patients treated with standard nCRT (fluorouracil + leucovorin + radiotherapy) was analyzed. Clinical response was assessed by tumor regression grade (TRG). Seven patients with extreme responses – good (3 TRG1 and 2 TRG2) and poor (2 TRG5) were selected for whole-exome sequencing (WES). Candidate predictive variants were identified based on their differential presence between responder and nonresponder groups and biological relevance (localization in coding region or regulatory elements and enzyme-altering effects). Selected variants were validated in 29 moderate-response patients (15 TRG3 and 14 TRG4) by targeted sequencing. Results: Two genetic variants were selected according to the criteria outlined above: rs149012039, which is located within the CYP2D7 pseudogene and represents a frameshift variant, and rs3093200, which is located in the first exon of the CYP4F2 gene and has a damaging effect on the protein. Validation in the remaining samples showed that neither variant was present in patients with a moderate response to therapy. Conclusions: The presence of variants rs149012039 and rs3093200 in individuals with a good clinical response and their absence in individuals with a moderate or poor response supports their potential as predictive biological markers for response to nCRT in rectal cancer