ATP Binding Cassette B1 (ABCB1) is a transporter with a broad substrate specificity involved in the elimination of several carcinogens from the gut. Several polymorphic variants within the ABCB1 gene have been reported as modulators of ABCB1-mediated transport. We investigated the impact of ABCB1 genetic variants on colorectal cancer (CRC) risk. A hybrid tagging/functional approach was performed to select 28 single nucleotide polymorphisms (SNPs) that were genotyped in 1,321 Czech subjects, 699 CRC cases and 622 controls. In addition, six potentially functional SNPs were genotyped in 3,662 German subjects, 1,809 cases and 1,853 controls from the DACHS study. We found that three functional SNPs (rs1202168, rs1045642 and rs868755) were associated with CRC risk in the German population. Carriers of the rs1202168_T and rs868755_T alleles had an increased risk for CRC (P(trend) = 0.016 and 0.029, respectively), while individuals bearing the rs1045642_C allele showed a decreased risk of CRC (P(trend) = 0.022). We sought to replicate the most significant results in an independent case-control study of 3,803 subjects, 2,169 cases and 1,634 controls carried out in the North of Germany. None of the SNPs tested were significantly associated with CRC risk in the replication study. In conclusion, in this study of about 8,800 individuals we show that ABCB1 gene polymorphisms play at best a minor role in the susceptibility to CRC.

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

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Ferlay J, Parkin DM, Steliarova-Foucher E. Estimates of cancer incidence and mortality in Europe in 2008. Eur J Cancer. 2010;46:765–781. PubMed

Ferlay J, Shin HR, Bray F, Forman D, Mathers C, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010 PubMed

Andersen V, Agerstjerne L, Jensen D, Ostergaard M, Saebo M, et al. The multidrug resistance 1 (MDR1) gene polymorphism G-rs3789243-A is not associated with disease susceptibility in Norwegian patients with colorectal adenoma and colorectal cancer; a case control study. BMC Med Genet. 2009;10:18. PubMed PMC

Campa D, Pardini B, Naccarati A, Vodickova L, Novotny J, et al. A gene-wide investigation on polymorphisms in the ABCG2/BRCP transporter and susceptibility to colorectal cancer. Mutat Res. 2008;645:56–60. PubMed

de la Chapelle A. Genetic predisposition to colorectal cancer. Nat Rev Cancer. 2004;4:769–780. PubMed

Huxley RR, Ansary-Moghaddam A, Clifton P, Czernichow S, Parr CL, et al. The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence. Int J Cancer. 2009;125:171–180. PubMed

Slattery ML, Curtin K, Anderson K, Ma KN, Ballard L, et al. Associations between cigarette smoking, lifestyle factors, and microsatellite instability in colon tumors. J Natl Cancer Inst. 2000;92:1831–1836. PubMed

Carrai M, Steinke V, Vodicka P, Pardini B, Rahner N, et al. Association Between TAS2R38 Gene Polymorphisms and Colorectal Cancer Risk: A Case-Control Study in Two Independent Populations of Caucasian Origin. PLoS One. 2011;6:e20464. PubMed PMC

Hughes D, Hlavata I, Soucek P, Pardini B, Naccarati A, et al. Ornithine Decarboxylase G316A Genotype and Colorectal Cancer Risk. Colorectal Dis 2010 PubMed

Hughes DJ, Hlavata I, Soucek P, Pardini B, Naccarati A, et al. Variation in the Vitamin D Receptor Gene is not Associated with Risk of Colorectal Cancer in the Czech Republic. J Gastrointest Cancer 2010 PubMed

Landi D, Moreno V, Guino E, Vodicka P, Pardini B, et al. Polymorphisms affecting micro-RNA regulation and associated with the risk of dietary-related cancers: A review from the literature and new evidence for a functional role of rs17281995 (CD86) and rs1051690 (INSR), previously associated with colorectal cancer. Mutat Res 2010 PubMed

Santarelli RL, Pierre F, Corpet DE. Processed meat and colorectal cancer: a review of epidemiologic and experimental evidence. Nutr Cancer. 2008;60:131–144. PubMed PMC

Greiner B, Eichelbaum M, Fritz P, Kreichgauer HP, von Richter O, et al. The role of intestinal P-glycoprotein in the interaction of digoxin and rifampin. J Clin Invest. 1999;104:147–153. PubMed PMC

Thiebaut F, Tsuruo T, Hamada H, Gottesman MM, Pastan I, et al. Cellular localization of the multidrug-resistance gene product P-glycoprotein in normal human tissues. Proc Natl Acad Sci U S A. 1987;84:7735–7738. PubMed PMC

Dietrich CG, Geier A, Oude Elferink RP. ABC of oral bioavailability: transporters as gatekeepers in the gut. Gut. 2003;52:1788–1795. PubMed PMC

Walle UK, Walle T. Transport of the cooked-food mutagen 2-amino-1-methyl-6-phenylimidazo-[4,5-b]pyridine (PhIP) across the human intestinal Caco-2 cell monolayer: role of efflux pumps. Carcinogenesis. 1999;20:2153–2157. PubMed

Penny JI, Campbell FC. Active transport of benzo[a]pyrene in apical membrane vesicles from normal human intestinal epithelium. Biochim Biophys Acta. 1994;1226:232–236. PubMed

Phang JM, Poore CM, Lopaczynska J, Yeh GC. Flavonol-stimulated efflux of 7,12-dimethylbenz(a)anthracene in multidrug-resistant breast cancer cells. Cancer Res. 1993;53:5977–5981. PubMed

van Herwaarden AE, Jonker JW, Wagenaar E, Brinkhuis RF, Schellens JH, et al. The breast cancer resistance protein (Bcrp1/Abcg2) restricts exposure to the dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine. Cancer Res. 2003;63:6447–6452. PubMed

Gurney H, Wong M, Balleine RL, Rivory LP, McLachlan AJ, et al. Imatinib disposition and ABCB1 (MDR1, P-glycoprotein) genotype. Clin Pharmacol Ther. 2007;82:33–40. PubMed

Capron A, Mourad M, De Meyer M, De Pauw L, Eddour DC, et al. CYP3A5 and ABCB1 polymorphisms influence tacrolimus concentrations in peripheral blood mononuclear cells after renal transplantation. Pharmacogenomics. 2010;11:703–714. PubMed

Buda G, Ricci D, Huang CC, Favis R, Cohen N, et al. Polymorphisms in the multiple drug resistance protein 1 and in P-glycoprotein 1 are associated with time to event outcomes in patients with advanced multiple myeloma treated with bortezomib and pegylated liposomal doxorubicin. Ann Hematol. 2010;89:1133–1140. PubMed PMC

Hoffmeyer S, Burk O, von Richter O, Arnold HP, Brockmoller J, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000;97:3473–3478. PubMed PMC

Mickley LA, Lee JS, Weng Z, Zhan Z, Alvarez M, et al. Genetic polymorphism in MDR-1: a tool for examining allelic expression in normal cells, unselected and drug-selected cell lines, and human tumors. Blood. 1998;91:1749–1756. PubMed

Campa D, Gioia A, Tomei A, Poli P, Barale R. Association of ABCB1/MDR1 and OPRM1 gene polymorphisms with morphine pain relief. Clin Pharmacol Ther. 2008;83:559–566. PubMed

Panczyk M, Balcerczak E, Piaskowski S, Jamroziak K, Pasz-Walczak G, et al. ABCB1 gene polymorphisms and haplotype analysis in colorectal cancer. Int J Colorectal Dis. 2009;24:895–905. PubMed

Atalay C, Demirkazik A, Gunduz U. Role of ABCB1 and ABCC1 gene induction on survival in locally advanced breast cancer. J Chemother. 2008;20:734–739. PubMed

Johnatty SE, Beesley J, Paul J, Fereday S, Spurdle AB, et al. ABCB1 (MDR 1) polymorphisms and progression-free survival among women with ovarian cancer following paclitaxel/carboplatin chemotherapy. Clin Cancer Res. 2008;14:5594–5601. PubMed

Shitara K, Matsuo K, Ito S, Sawaki A, Kawai H, et al. Effects of Genetic Polymorphisms in the ABCB1 Gene on Clinical Outcomes in Patients with Gastric Cancer Treated by Second-line Chemotherapy. Asian Pac J Cancer Prev. 2010;11:447–452. PubMed

Balcerczak E, Panczyk M, Piaskowski S, Pasz-Walczak G, Salagacka A, et al. ABCB1/MDR1 gene polymorphisms as a prognostic factor in colorectal cancer. Int J Colorectal Dis. 2010;25:1167–1176. PubMed PMC

Jamroziak K, Mlynarski W, Balcerczak E, Mistygacz M, Trelinska J, et al. Functional C3435T polymorphism of MDR1 gene: an impact on genetic susceptibility and clinical outcome of childhood acute lymphoblastic leukemia. Eur J Haematol. 2004;72:314–321. PubMed

De Iudicibus S, De Pellegrin A, Stocco G, Bartoli F, Bussani R, et al. ABCB1 gene polymorphisms and expression of P-glycoprotein and long-term prognosis in colorectal cancer. Anticancer Res. 2008;28:3921–3928. PubMed

Kurzawski M, Drozdzik M, Suchy J, Kurzawski G, Bialecka M, et al. Polymorphism in the P-glycoprotein drug transporter MDR1 gene in colon cancer patients. Eur J Clin Pharmacol. 2005;61:389–394. PubMed

Petrova DT, Nedeva P, Maslyankov S, Toshev S, Yaramov N, et al. No association between MDR1 (ABCB1) 2677G>T and 3435C>T polymorphism and sporadic colorectal cancer among Bulgarian patients. J Cancer Res Clin Oncol. 2008;134:317–322. PubMed

Tomlinson IP, Dunlop M, Campbell H, Zanke B, Gallinger S, et al. COGENT (COlorectal cancer GENeTics): an international consortium to study the role of polymorphic variation on the risk of colorectal cancer. Br J Cancer. 102:447–454. PubMed PMC

Campa D, Pardini B, Naccarati A, Vodickova L, Novotny J, et al. Polymorphisms of genes coding for ghrelin and its receptor in relation to colorectal cancer risk: a two-step gene-wide case-control study. BMC Gastroenterol. 2010;10:112. PubMed PMC

Brenner H, Chang-Claude J, Seiler CM, Rickert A, Hoffmeister M. Protection from colorectal cancer after colonoscopy: a population-based, case-control study. Ann Intern Med. 154:22–30. PubMed

Schafmayer C, Buch S, Volzke H, von Schonfels W, Egberts JH, et al. Investigation of the colorectal cancer susceptibility region on chromosome 8q24.21 in a large German case-control sample. Int J Cancer. 2009;124:75–80. PubMed

Carlson CS, Eberle MA, Rieder MJ, Yi Q, Kruglyak L, et al. Selecting a maximally informative set of single-nucleotide polymorphisms for association analyses using linkage disequilibrium. Am J Hum Genet. 2004;74:106–120. PubMed PMC

Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21:263–265. PubMed

de Bakker PI, Yelensky R, Pe'er I, Gabriel SB, Daly MJ, et al. Efficiency and power in genetic association studies. Nat Genet. 2005;37:1217–1223. PubMed

Sissung TM, Baum CE, Deeken J, Price DK, Aragon-Ching J, et al. ABCB1 genetic variation influences the toxicity and clinical outcome of patients with androgen-independent prostate cancer treated with docetaxel. Clin Cancer Res. 2008;14:4543–4549. PubMed PMC

Lu PH, Wei MX, Yang J, Liu X, Tao GQ, et al. Association between two polymorphisms of ABCB1 and breast cancer risk in the current studies: a meta-analysis. Breast Cancer Res Treat 2010 PubMed

Sauna ZE, Kimchi-Sarfaty C, Ambudkar SV, Gottesman MM. Silent polymorphisms speak: how they affect pharmacogenomics and the treatment of cancer. Cancer Res. 2007;67:9609–9612. PubMed

Potocnik U, Ferkolj I, Glavac D, Dean M. Polymorphisms in multidrug resistance 1 (MDR1) gene are associated with refractory Crohn disease and ulcerative colitis. Genes Immun. 2004;5:530–539. PubMed

Campa D, McKay J, Sinilnikova O, Husing A, Vogel U, et al. Genetic variation in genes of the fatty acid synthesis pathway and breast cancer risk. Breast Cancer Res Treat. 2009;118:565–574. PubMed

Campa D, Vodicka P, Pardini B, Naccarati A, Carrai M, et al. A gene-wide investigation on polymorphisms in the taste receptor 2R14 (TAS2R14) and susceptibility to colorectal cancer. BMC Med Genet. 2010;11:88. PubMed PMC

Sainz J, Rudolph A, Hein R, Hoffmeister M, Buch S, et al. Association of genetic polymorphisms in ESR2, HSD17B1, ABCB1, and SHBG genes with colorectal cancer risk. Endocr Relat Cancer. 2011;18:265–276. PubMed

Chen B, Wilkening S, Drechsel M, Hemminki K. SNP_tools: A compact tool package for analysis and conversion of genotype data for MS-Excel. BMC Res Notes. 2009;2:214. PubMed PMC

Gabriel SB, Schaffner SF, Nguyen H, Moore JM, Roy J, et al. The structure of haplotype blocks in the human genome. Science. 2002;296:2225–2229. PubMed

Li J, Ji L. Adjusting multiple testing in multilocus analyses using the eigenvalues of a correlation matrix. Heredity. 2005;95:221–227. PubMed

Nyholt DR. A simple correction for multiple testing for single-nucleotide polymorphisms in linkage disequilibrium with each other. Am J Hum Genet. 2004;74:765–769. PubMed PMC

Kim RB, Leake BF, Choo EF, Dresser GK, Kubba SV, et al. Identification of functionally variant MDR1 alleles among European Americans and African Americans. Clin Pharmacol Ther. 2001;70:189–199. PubMed

Brenner H, Chang-Claude J, Seiler CM, Sturmer T, Hoffmeister M. Does a negative screening colonoscopy ever need to be repeated? Gut. 2006;55:1145–1150. PubMed PMC

Ho GT, Nimmo ER, Tenesa A, Fennell J, Drummond H, et al. Allelic variations of the multidrug resistance gene determine susceptibility and disease behavior in ulcerative colitis. Gastroenterology. 2005;128:288–296. PubMed

Ichihara S, Yamada Y, Kato K, Hibino T, Yokoi K, et al. Association of a polymorphism of ABCB1 with obesity in Japanese individuals. Genomics. 2008;91:512–516. PubMed

Andersen V, Ostergaard M, Christensen J, Overvad K, Tjonneland A, et al. Polymorphisms in the xenobiotic transporter Multidrug Resistance 1 (MDR1) and interaction with meat intake in relation to risk of colorectal cancer in a Danish prospective case-cohort study. BMC Cancer. 2009;9:407. PubMed PMC

Khedri A, Nejat-Shokouhi A, Salek R, Esmaeili H, Mokhtarifar A, et al. Association of the colorectal cancer and MDR1 gene polymorphism in an Iranian population. Mol Biol Rep. 2010;38:2939–2943. PubMed

Osswald E, Johne A, Laschinski G, Arjomand-Nahad F, Malzahn U, et al. Association of MDR1 genotypes with susceptibility to colorectal cancer in older non-smokers. Eur J Clin Pharmacol. 2007;63:9–16. PubMed

Bae SY, Choi SK, Kim KR, Park CS, Lee SK, et al. Effects of genetic polymorphisms of MDR1, FMO3 and CYP1A2 on susceptibility to colorectal cancer in Koreans. Cancer Sci. 2006;97:774–779. PubMed PMC

Kimchi-Sarfaty C, Oh JM, Kim IW, Sauna ZE, Calcagno AM, et al. A “silent” polymorphism in the MDR1 gene changes substrate specificity. Science. 2007;315:525–528. PubMed

Broderick P, Carvajal-Carmona L, Pittman AM, Webb E, Howarth K, et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet. 2007;39:1315–1317. PubMed

Jaeger E, Webb E, Howarth K, Carvajal-Carmona L, Rowan A, et al. Common genetic variants at the CRAC1 (HMPS) locus on chromosome 15q13.3 influence colorectal cancer risk. Nat Genet. 2008;40:26–28. PubMed

Lascorz J, Forsti A, Chen B, Buch S, Steinke V, et al. Genome-wide association study for colorectal cancer identifies risk polymorphisms in German familial cases and implicates MAPK signalling pathways in disease susceptibility. Carcinogenesis. 2010;31:1612–1619. PubMed

Tenesa A, Farrington SM, Prendergast JG, Porteous ME, Walker M, et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet. 2008;40:631–637. PubMed PMC

Tomlinson IP, Webb E, Carvajal-Carmona L, Broderick P, Howarth K, et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet. 2008;40:623–630. PubMed

Vineis P, Brennan P, Canzian F, Ioannidis JP, Matullo G, et al. Expectations and challenges stemming from genome-wide association studies. Mutagenesis. 2008;23:439–444. PubMed

Association between polymorphisms of TAS2R16 and susceptibility to colorectal cancer