title: 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 haematological 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 drug-metabolizing 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 versus control group. The homozygous genotype C/C in the (rs562) ABCC5 gene occurred in 6/9 patients with GI toxicity versus 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 versus 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's exact test (two tailed) and relevant SNPs were further analyzed by direct sequencing. We have identified 3 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.
authors: Magna Graecia University and Tommaso Campanella Cancer Center; Catanzaro, Italy.
authors: Maria Teresa
authors: MT
authors: Di Martino
authors: Mariamena
authors: M
authors: Arbitrio
authors: Emanuela
authors: E
authors: Leone
authors: Pietro Hiram
authors: PH
authors: Guzzi
authors: Maria Saveria
authors: MS
authors: Rotundo
authors: Domenico
authors: D
authors: Ciliberto
authors: Vera
authors: V
authors: Tomaino
authors: Fernanda
authors: F
authors: Fabiani
authors: Danilo
authors: D
authors: Talarico
authors: Pasquale
authors: P
authors: Sperlongano
authors: Patrizia
authors: P
authors: Doldo
authors: Mario
authors: M
authors: Cannataro
authors: Michele
authors: M
authors: Caraglia
authors: Pierfrancesco
authors: P
authors: Tassone
authors: Pierosandro
authors: P
authors: Tagliaferri
mesh_terms: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics*; D000368:Aged; D000483:Alleles; D000972:Antineoplastic Agents, Phytogenic / Q000009:adverse effects* / Q000627:therapeutic use; D002166:Camptothecin / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D015179:Colorectal Neoplasms / Q000150:complications* / Q000188:drug therapy / Q000235:genetics; D005260:Female; D005767:Gastrointestinal Diseases / Q000139:chemically induced* / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D000077146:Irinotecan; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D020641:Polymorphism, Single Nucleotide
chemical_list: D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D000972:Antineoplastic Agents, Phytogenic; D002166:Camptothecin; D000077146:Irinotecan; D027425:ATP-Binding Cassette, Sub-Family C Proteins; C120809:ABCC5 protein, human; C419353:ABCG1 protein, human