Pharmacogenetic and pharmacoepigenetic factors for irinotecan drug response in colon cancer treatment

SN-38 is the active metabolite of the pro-drug irinotecan which is metabolized by which is commonly used in the treatment of metastatic colon cancer. Genetic and epigenetic factors that affect enzyme activity put forward the rational use of drugs. In this study, it is aimed to have predictive data about the outcomes of the genetic and epigenetic factors that may affect UGT1A1 expression on irinotecan drug. This study comprises a total of 48 patients treated with irinotecan. Toxic effect, most commonly diarrhea, mucositis and neutropenia was observed in 66,6% of the patients. The distribution of the genotypes was as follows: 72,98% of them wild type UGT1A1 1*/1* and 6,5% of them recessive UGT1A1 28*/28*. Blood samples of 9 patients and 13 colon tissue samples of 8 patients were collected for epigenetics studies. The methylation profiles of 3rd, 4th, 28th, 29th, and 30th CpG dinucleotides located upstream of transcription start site was investigated. The methylation of -4 CpG dinucleotide in promoter region and -28 CpG and -29 CpG dinucleotides in distal enhancer were detected. Blood samples showed high methylation profiles in all regions compared to tissue samples. UGT1A1 genotypes, patient lifestyle, demographic factors, combined drug use and UGT1A1 CpG dinucleotide methylations were examined by multiple or binary logistic regression model. There was no significant relationship between these factors. This is the first study for the methylation pattern for UGT1A1 in blood samples showing epigenetic regulation might be by tissue-specific methylation of UGT1A1. It is also the first study with irinotecan pharmacoepigenetic so far in Türkiye.