Single nucleotide polymorphisms of ABCC5 and ABCG1 transporter genes correlate to irinotecan-associated gastrointestinal toxicity in colorectal cancer patients: A DMET microarray profiling study

摘要

Recent findings have disclosed the role of UD P-glucuronosyltransferase (UGT) 1A1*28 on the hematological toxicity induced by irinotecan (CPT-11), a drug commonly used in the treatment of metastatic colorectal cancer (mCRC). We investigated the pharmacogenomic profile of irinotecan-induced gastrointestinal (GI) toxicity by the novel drugmetabolizing enzyme and transporter (DMET) microarray genotyping platform. Twenty-six mCRC patients who had undergone to irinotecan-based chemotherapy were enrolled in a case [patients experiencing ≥ grade 3 gastrointestinal, (GI) toxicity] -control (matched patients without GI toxicity) study. A statistically significant difference of SNP genotype distribution was found in the case vs. control group. The homozygous genotype C/C in the (rs562) ABCC5 gene occurred in 6/9 patients with GI toxicity vs. 1/17 patients without GI toxicity (p = 0.0022). The homozygous genotype G/G in the (rs425215) ABCG1 was found in 7/9 patients with GI toxicity vs. 4/17 patients without GI toxicity (p = 0.0135). The heterozygous genotype G/A in the 388G > A (rs2306283) OATP1B1/SLCO1B1 was found in 3/9 patients with grade ≥3 GI toxicity vs. 14/17 patients without GI toxicity (p = 0.0277). DNA extracted from peripheral blood cells was genotyped by DMET Plus chip on Affymetrix array system. Genotype association was calculated by Fisher exact test (two tailed) and relevant SNPs were further analyzed by direct sequencing. We have identified three SNPs mapping in ABCG1, ABCC5 and OATP1B1/SLCO1B1 transporter genes associated with GI toxicity induced by irinotecan in mCRC patients expanding the available knowledge of irinogenomics. The DMET microarray platform is an emerging technology for easy identification of new genetic variants for personalized medicine.