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

Abstract

Recent findings have disclosed the role of udP-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.

ABCC5 and ABCG1 polymorphisms predict irinotecan-induced severe toxicity in metastatic colorectal cancer patients

“…SLCO1B1 encodes the SLC organic anion transporter, which mediates the hepatic influx of SN-38 from the blood [22]. One SLCO1B1 variant (*1b; 388A > G) was associated with an increased risk of gastrointestinal toxicity and an increased absolute neutrophil count in a small study of 26 patients [27]. In contrast, 521T > C was linked to decreased toxicity in 56 patients [28].…”

Clinical usefulness of testing for UDP glucuronosyltransferase 1 family, polypeptide A1 polymorphism prior to the inititation of irinotecan-based chemotherapy

“…However, the association between UGT1A1 polymorphism and irinotecan-induced diarrhea has been controversial. In addition to UGT1A1 polymorphisms, an association between irinotecan-induced gastrointestinal toxicity and polymorphisms of the ABCC5, ABCG1 and SLCO1B1 genes has also been reported (26).…”

Comparative Analysis of <i>UGT1A9</i> Genetic Polymorphisms between Chinese Han and Tibetan Populations

“…Clinical testing for the UGT1A9 polymorphisms should be implemented as predictors of toxicity/effectiveness of some drugs. In this regard, systematically studying the polymorphisms of UGT1A9 might play an important role in the prediction of toxicity and responsiveness to cytotoxic agents, as described for other detoxifying enzymes (Martino et al, 2011).…”