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

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 versus 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.

[1]  Soma Das,et al.  Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. , 2004, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  Balázs Sarkadi,et al.  The role of ABC transporters in drug absorption, distribution, metabolism, excretion and toxicity (ADME-Tox). , 2008, Drug discovery today.

[3]  Balram Chowbay,et al.  Pharmacogenetics of SLCO1B1 gene and the impact of *1b and *15 haplotypes on irinotecan disposition in Asian cancer patients , 2006, Pharmacogenetics and genomics.

[4]  J. Verweij,et al.  Impact of body-size measures on irinotecan clearance: alternative dosing recommendations. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  J. Verweij,et al.  Role of pharmacogenetics in irinotecan therapy. , 2006, Cancer letters.

[6]  H. McLeod,et al.  UGT1A and irinotecan toxicity: keeping it in the family. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[7]  M. Fitzgerald,et al.  ABC transporters, atherosclerosis and inflammation. , 2010, Atherosclerosis.

[8]  Federico Innocenti,et al.  Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  C. Beglinger,et al.  MAPPING OF MULTIDRUG RESISTANCE GENE 1 AND MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN ISOFORM 1 TO 5 mRNA EXPRESSION ALONG THE HUMAN INTESTINAL TRACT , 2005, Drug Metabolism and Disposition.

[10]  Ronald W. Davis,et al.  Multiplexed genotyping with sequence-tagged molecular inversion probes , 2003, Nature Biotechnology.

[11]  R. Kerb.  Implications of genetic polymorphisms in drug transporters for pharmacotherapy. , 2006, Cancer letters.

[12]  P. Borst,et al.  Mammalian ABC transporters in health and disease. , 2002, Annual review of biochemistry.

[13]  Paul T Tarr,et al.  Emerging new paradigms for ABCG transporters. , 2009, Biochimica et biophysica acta.

[14]  Henk-Jan Guchelaar,et al.  Clinical and pharmacogenetic factors associated with irinotecan toxicity. , 2008, Cancer treatment reviews.

[15]  J. Verweij,et al.  Irinotecan‐induced Diarrhea: Functional Significance of the Polymorphic ABCC2 Transporter Protein , 2007, Clinical pharmacology and therapeutics.

[16]  P. Hardenbol,et al.  Comprehensive assessment of metabolic enzyme and transporter genes using the Affymetrix Targeted Genotyping System. , 2007, Pharmacogenomics.

[17]  Paul T. Tarr,et al.  ABCG1 has a critical role in mediating cholesterol efflux to HDL and preventing cellular lipid accumulation. , 2005, Cell metabolism.

[18]  J. Berlin,et al.  Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. , 2004, The New England journal of medicine.

[19]  D. Keppler,et al.  The Multidrug Resistance Protein 5 Functions as an ATP-dependent Export Pump for Cyclic Nucleotides* , 2000, The Journal of Biological Chemistry.

[20]  P. Tagliaferri,et al.  Site-selective cAMP analogs at micromolar concentrations induce growth arrest and differentiation of acute promyelocytic, chronic myelocytic, and acute lymphocytic human leukemia cell lines. , 1988, Blood.

[21]  U. Hofmann,et al.  Acute effects of pravastatin on cholesterol synthesis are associated with SLCO1B1 (encoding OATP1B1) haplotype *17 , 2005, Pharmacogenetics and genomics.

[22]  J. Robert,et al.  Pharmacogenetics of human carboxylesterase 2, an enzyme involved in the activation of irinotecan into SN‐38 , 2004, Clinical pharmacology and therapeutics.

[23]  Placido Bramanti,et al.  CYP4F2 genetic variant (rs2108622) significantly contributes to warfarin dosing variability in the Italian population. , 2009, Pharmacogenomics.

[24]  M. Hayden,et al.  Carriers of Loss-of-Function Mutations in ABCA1 Display Pancreatic β-Cell Dysfunction , 2008, Diabetes Care.

[25]  N. Meropol,et al.  UGT1A7 and UGT1A9 polymorphisms predict response and toxicity in colorectal cancer patients treated with capecitabine/irinotecan. , 2005, Clinical cancer research : an official journal of the American Association for Cancer Research.

[26]  M. Ratain,et al.  Haplotypes of variants in the UDP-glucuronosyltransferase1A9 and 1A1 genes , 2005, Pharmacogenetics and genomics.

[27]  M. Narabayashi,et al.  Genetic linkage of UGT1A7 and UGT1A9 polymorphisms to UGT1A1*6 is associated with reduced activity for SN-38 in Japanese patients with cancer , 2007, Cancer Chemotherapy and Pharmacology.

[28]  Terence P. Speed,et al.  Genome analysis A genotype calling algorithm for affymetrix SNP arrays , 2005 .

[29]  R. James,et al.  Irinotecan combined with fluorouracil compared with fluorouracil alone as first-line treatment for metastatic colorectal cancer: a multicentre randomised trial , 2000, The Lancet.

[30]  Hyeong-Seok Lim,et al.  Influence of the organic anion-transporting polypeptide 1B1 (OATP1B1) polymorphisms on irinotecan-pharmacokinetics and clinical outcome of patients with advanced non-small cell lung cancer. , 2008, Lung cancer.

[31]  G. Schmitz,et al.  ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[32]  J P Pignon,et al.  Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. , 2001, The New England journal of medicine.

[33]  Mario Cannataro,et al.  A peroxisome proliferator-activated receptor gamma (PPARG) polymorphism is associated with zoledronic acid-related osteonecrosis of the jaw in multiple myeloma patients: analysis by DMET microarray profiling , 2011, British journal of haematology.

[34]  Sang Gyun Kim,et al.  8‐Cl‐cAMP induces cell cycle‐specific apoptosis in human cancer cells , 2001, International journal of cancer.

[35]  S. Steinberg,et al.  A pharmacogenetic study of docetaxel and thalidomide in patients with castration-resistant prostate cancer using the DMET genotyping platform , 2010, The Pharmacogenomics Journal.

[36]  Y. Turpaz,et al.  CYP4F2 genetic variant alters required warfarin dose. , 2008, Blood.

[37]  Shigeki Sugiura,et al.  ROLE OF ORGANIC ANION TRANSPORTER OATP1B1 (OATP-C) IN HEPATIC UPTAKE OF IRINOTECAN AND ITS ACTIVE METABOLITE, 7-ETHYL-10-HYDROXYCAMPTOTHECIN: IN VITRO EVIDENCE AND EFFECT OF SINGLE NUCLEOTIDE POLYMORPHISMS , 2005, Drug Metabolism and Disposition.

[38]  Soma Das,et al.  Comprehensive pharmacogenetic analysis of irinotecan neutropenia and pharmacokinetics. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  A. Sparreboom,et al.  Pharmacogenomics of ABC transporters and its role in cancer chemotherapy. , 2003, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[40]  C. Hedrick,et al.  A Critical Role for ABCG1 in Macrophage Inflammation and Lung Homeostasis1 , 2008, The Journal of Immunology.

[41]  L. Saltz,et al.  Irinotecan plus fluorouracil and leucovorin for metastatic colorectal cancer. Irinotecan Study Group. , 2000, The New England journal of medicine.

[42]  Taylor J. Maxwell,et al.  Irinotecan Pharmacogenetics: Influence of Pharmacodynamic Genes , 2008, Clinical Cancer Research.