Mutation Research 645 (2008) 56–60 Contents lists available at ScienceDirect Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis journal homepage: www.elsevier.com/locate/molmut Community address: www.elsevier.com/locate/mutres Short communication A gene-wide investigation on polymorphisms in the ABCG2/BRCP transporter and susceptibility to colorectal cancer Daniele Campa a,b , Barbara Pardini c , Alessio Naccarati c , Ludmila Vodickova c , Jan Novotny d , Asta Försti a,e , Kari Hemminki a,e , Roberto Barale b , Pavel Vodicka c , Federico Canzian a,∗ a German Cancer Research Center (DKFZ), Heidelberg, Germany b Department of Biology, University of Pisa, Pisa, Italy c Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic d Department of Oncology, First Faculty of Medicine, Charles University, Prague, Czech Republic e Center for Family and Community Medicine, Karolinska Institute, Huddinge, Sweden article info Article history: Received 3 July 2008 Received in revised form 31 July 2008 Accepted 1 August 2008 Available online 19 August 2008 Keywords: ABCG2 BRCP Transporter Colorectal cancer Polymorphisms Susceptibility abstract ATP-binding cassette (ABC) transporters actively export a wide variety of molecules from cells, contribut- ing to reduce the local cellular burden of toxic compounds. ABCG2/BCRP is abundantly expressed in epithelial cells of the intestine and colon. The expression and activity of this transporter in the gut differ between individuals, due at least in part to genetic polymorphisms, which may thus affect the risk of col- orectal cancer (CRC). We selected 15 tagging SNPs, covering all the known genetic variation of the gene, and typed them in 680 CRC cases and 593 controls. We found that heterozygous carriers of the minor alleles of SNPs rs2622621 and rs1481012 had a decreased risk of CRC, respectively, with odds ratios of 0.73 (95% confidence interval 0.56–0.94; P value = 0.017), and 0.72 (95% CI 0.53–0.97; P value = 0.03). Thus, we found no strong and clearcut association between ABCG2 polymorphisms and CRC risk. To our knowledge this is the first report on ABCG2 and CRC risk. © 2008 Elsevier B.V. All rights reserved. 1. Introduction The ATP-binding cassette (ABC) transporter superfamily is among the largest and most broadly expressed protein superfam- ilies known. The vast majority of its members are responsible for the active transport of a wide variety of compounds across biological membranes, including phospholipids, ions, pep- tides, steroids, polysaccharides, amino acids, organic anions, bile acids, drugs, and other xenobiotics [1–3]. In humans, 48 ABC genes that are organized into seven subfamilies (A–G) have been described, several of which are involved in well-defined genetic disorders [1,3,4] (http://nutrigene.4t.com/humanabc.htm, http://www.gene.ucl.ac.uk/nomenclature/genefamily/abc.htm). The major role of ABC transporters is to reduce the local cellular burden of toxic compounds, giving the individual cell a protection against toxic effects. These export pumps are primarily expressed in the apical membrane of epithelial cells, such as enterocytes, ∗ Corresponding author at: Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany. Tel.: +49 6221 421791; fax: +49 6221 421810. E-mail address: f.canzian@dkfz.de (F. Canzian). which are exposed to xenobiotics. In these cells the same trans- porters function on the one hand to reduce the entrance of harmful substances and on the other hand to eliminate their detoxification products. The first function (i.e. direct elimination of xenobiotics entering the cell) represents a first defense line against xenobiotics and can be called “phase 0 metabolism”, indicating the close con- nection to the activation and conjugation steps of detoxification [3]. Likewise, the latter step has been called “phase III metabolism” [5]. It should be taken into account that phase 0 results from the balance of the import of substances into cells, regulated by solute carrier transporters, and the export, regulated by ABC transporters. In particular, ABCG2/BCRP is expressed abundantly in the api- cal membrane of normal intestinal and colonic epithelium in vivo [6]. ABCG2 is believed to function as a component of the organism’s defense against toxicity by restricting the entrance of genotoxins from the intestinal tract into the organism and by facilitating the removal of toxic metabolites from the organ- ism via bile or urine [7–9]. Among dietary genotoxins exported by ABCG2 is the meat-derived heterocyclic amine 2-amino-1- methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) [9]. Thus, ABCG2 may prevent the intestinal epithelial cells from exposure to such genotoxins and hence provide protection against chemical-induced carcinogenesis. 0027-5107/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.mrfmmm.2008.08.001