BACKGROUND: Genetics plays an important role in the susceptibility to sporadic colorectal cancer (CRC). In the last 10 years genome-wide association studies (GWAS) have identified over 40 independent low penetrance polymorphic variants. However, these loci only explain around 1‑4% of CRC heritability, highlighting the dire need of identifying novel risk loci. In this study, we focused our attention on the genetic variability of the TAS2R16 gene, encoding for one of the bitter taste receptors that selectively binds to salicin, a natural antipyretic that resembles aspirin. Given the importance of inflammation in CRC, we tested whether polymorphic variants in this gene could affect the risk of developing this neoplasia hypothesizing a role of TAS2R16 in modulating chronic inflammation within the gut. METHODS: We performed an association study using 6 tagging SNPs, (rs860170, rs978739, rs1357949, rs1525489, rs6466849, rs10268496) that cover all TAS2R16 genetic variability. The study was carried out on 1902 CRC cases and 1532 control individuals from four European countries. RESULTS: We did not find any statistically significant association between risk of developing CRC and selected SNPs. However, after stratification by histology (colon vs. rectum) we found that rs1525489 was associated with increased risk of rectal cancer with a (Ptrend of = 0.0071). CONCLUSIONS: Our data suggest that polymorphisms within TAS2R16 gene do not have a strong influence on colon cancer susceptibility, but a possible role in rectal cancer should be further evaluated in larger cohorts.

Biomedical Centre Medical School Pilsen Charles University Prague Pilsen Czech Republic

Cancer Prevention and Control Program Catalan Institute of Oncology IDIBELL CIBERESP and Department of Clinical Sciences Faculty of Medicine University of Barcelona Barcelona Spain

Department of Biology University of Pisa Via Derna 1 56100 Pisa Italy

Department of Gastroenterology Lithuanian University of Health Sciences Kaunas Lithuania

Department of Molecular Biology of Cancer Institute of Experimental Medicine Academy of Science of Czech Republic Prague Czech Republic

Division of Gastroenterology and Research Laboratory IRCCS Scientific Institute and Regional General Hospital Casa Sollievo della Sofferenza San Giovanni Rotondo Italy

Division of Molecular Genetic Epidemiology German Cancer Research Center Heidelberg Germany

Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany

Institute of Biology and Medical Genetics 1st Medical Faculty Charles University Prague Czech Republic

Zobrazit více v PubMed

Ervik FLM, Ferlay J, Mery L, Soerjomataram I, Bray F. Cancer Today. Lyon: International Agency for Research on Cancer; 2016. Available from: http://gco.iarc.fr/today. Accessed 20 Mar 2017.

Marley AR, Nan H. Epidemiology of colorectal cancer. Int J Mol Epidemiol Genet. 2016;7(3):105–114. PubMed PMC

Peters U, Bien S, Zubair N. Genetic architecture of colorectal cancer. Gut. 2015;64(10):1623–1636. doi: 10.1136/gutjnl-2013-306705. PubMed DOI PMC

Vymetalkova V, Pardini B, Rosa F, Di Gaetano C, Novotny J, Levy M, Buchler T, Slyskova J, Vodickova L, Naccarati A, et al. Variations in mismatch repair genes and colorectal cancer risk and clinical outcome. Mutagenesis. 2014;29(4):259–265. doi: 10.1093/mutage/geu014. PubMed DOI

Andersen V, Egeberg R, Tjonneland A, Vogel U. ABCC2 transporter gene polymorphisms, diet and risk of colorectal cancer: a Danish prospective cohort study. Scand J Gastroenterol. 2012;47(5):572–574. doi: 10.3109/00365521.2012.668933. PubMed DOI

Andersen V, Vogel U. Interactions between meat intake and genetic variation in relation to colorectal cancer. Genes Nutr. 2015;10(1):448. doi: 10.1007/s12263-014-0448-9. PubMed DOI PMC

Campa D, Pardini B, Naccarati A, Vodickova L, Novotny J, Forsti A, Hemminki K, Barale R, Vodicka P, Canzian F. A gene-wide investigation on polymorphisms in the ABCG2/BRCP transporter and susceptibility to colorectal cancer. Mutat Res. 2008;645(1–2):56–60. doi: 10.1016/j.mrfmmm.2008.08.001. PubMed DOI

Campa D, Pardini B, Naccarati A, Vodickova L, Novotny J, Steinke V, Rahner N, Holinski-Feder E, Morak M, Schackert HK, 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. doi: 10.1186/1471-230X-10-112. PubMed DOI PMC

Campa D, Sainz J, Pardini B, Vodickova L, Naccarati A, Rudolph A, Novotny J, Forsti A, Buch S, von Schonfels W, et al. A comprehensive investigation on common polymorphisms in the MDR1/ABCB1 transporter gene and susceptibility to colorectal cancer. PLoS One. 2012;7(3):e32784. doi: 10.1371/journal.pone.0032784. PubMed DOI PMC

Campa D, Vodicka P, Pardini B, Novotny J, Forsti A, Hemminki K, Barale R, Canzian F. Could polymorphisms in ATP-binding cassette C3/multidrug resistance associated protein 3 (ABCC3/MRP3) modify colorectal cancer risk? Eur J Cancer. 2008;44(6):854–857. doi: 10.1016/j.ejca.2008.02.004. PubMed DOI

Dik VK, Bueno-de-Mesquita HB, Van Oijen MG, Siersema PD, Uiterwaal CS, Van Gils CH, Van Duijnhoven FJ, Cauchi S, Yengo L, Froguel P, et al. Coffee and tea consumption, genotype-based CYP1A2 and NAT2 activity and colorectal cancer risk-results from the EPIC cohort study. Int J Cancer. 2014;135(2):401–412. doi: 10.1002/ijc.28655. PubMed DOI

Ferrari P, McKay JD, Jenab M, Brennan P, Canzian F, Vogel U, Tjonneland A, Overvad K, Tolstrup JS, Boutron-Ruault MC, et al. Alcohol dehydrogenase and aldehyde dehydrogenase gene polymorphisms, alcohol intake and the risk of colorectal cancer in the European prospective investigation into cancer and nutrition study. Eur J Clin Nutr. 2012;66(12):1303–1308. doi: 10.1038/ejcn.2012.173. PubMed DOI

Kopp TI, Andersen V, Tjonneland A, Vogel U. Polymorphisms in ATP-binding cassette transporter genes and interaction with diet and life style factors in relation to colorectal cancer in a Danish prospective case-cohort study. Scand J Gastroenterol. 2015;50(12):1469–1481. doi: 10.3109/00365521.2015.1056224. PubMed DOI

Liao LH, Zhang H, Lai MP, Lau KW, Lai AK, Zhang JH, Wang Q, Wei W, Chai JH, Lung ML, et al. The association of CYP2C9 gene polymorphisms with colorectal carcinoma in Han Chinese. Clin Chim Acta. 2007;380(1–2):191–196. doi: 10.1016/j.cca.2007.02.033. PubMed DOI

Landi S, Bottari F, Gemignani F, Gioia-Patricola L, Guino E, Osorio A, de Oca J, Capella G, Canzian F, Moreno V. Interleukin-4 and interleukin-4 receptor polymorphisms and colorectal cancer risk. Eur J Cancer. 2007;43(4):762–768. doi: 10.1016/j.ejca.2006.10.024. PubMed DOI

Landi S, Gemignani F, Bottari F, Gioia-Patricola L, Guino E, Cambray M, Biondo S, Capella G, Boldrini L, Canzian F, et al. Polymorphisms within inflammatory genes and colorectal cancer. J Nega Results Biomed. 2006;5:15. doi: 10.1186/1477-5751-5-15. PubMed DOI PMC

Vogel LK, Saebo M, Hoyer H, Kopp TI, Vogel U, Godiksen S, Frenzel FB, Hamfjord J, Bowitz-Lothe IM, Johnson E, et al. Intestinal PTGS2 mRNA levels, PTGS2 gene polymorphisms, and colorectal carcinogenesis. PLoS One. 2014;9(8):e105254. doi: 10.1371/journal.pone.0105254. PubMed DOI PMC

Rudolph A, Sainz J, Hein R, Hoffmeister M, Frank B, Forsti A, Brenner H, Hemminki K, Chang-Claude J. Modification of menopausal hormone therapy-associated colorectal cancer risk by polymorphisms in sex steroid signaling, metabolism and transport related genes. Endocr Relat Cancer. 2011;18(3):371–384. doi: 10.1530/ERC-11-0057. PubMed DOI

Sainz J, Rudolph A, Hoffmeister M, Frank B, Brenner H, Chang-Claude J, Hemminki K, Forsti A. Effect of type 2 diabetes predisposing genetic variants on colorectal cancer risk. J Clin Endocrinol Metab. 2012;97(5):E845–E851. doi: 10.1210/jc.2011-2565. PubMed DOI

Landi D, Gemignani F, Landi S. Role of variations within microRNA-binding sites in cancer. Mutagenesis. 2012;27(2):205–210. doi: 10.1093/mutage/ger055. PubMed DOI

Landi D, Gemignani F, Pardini B, Naccarati A, Garritano S, Vodicka P, Vodickova L, Canzian F, Novotny J, Barale R, et al. Identification of candidate genes carrying polymorphisms associated with the risk of colorectal cancer by analyzing the colorectal mutome and microRNAome. Cancer. 2012;118(19):4670–4680. doi: 10.1002/cncr.27435. PubMed DOI

Campa D, Vodicka P, Pardini B, Naccarati A, Carrai M, Vodickova L, Novotny J, Hemminki K, Forsti A, Barale R, 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. doi: 10.1186/1471-2350-11-88. PubMed DOI PMC

Carrai M, Steinke V, Vodicka P, Pardini B, Rahner N, Holinski-Feder E, Morak M, Schackert HK, Gorgens H, Stemmler S, 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(6):e20464. doi: 10.1371/journal.pone.0020464. PubMed DOI PMC

Schembre SM, Cheng I, Wilkens LR, Albright CL, Marchand le L. Variations in bitter-taste receptor genes, dietary intake, and colorectal adenoma risk. Nutr Cancer. 2013;65(7):982–990. doi: 10.1080/01635581.2013.807934. PubMed DOI PMC

Hinrichs AL, Wang JC, Bufe B, Kwon JM, Budde J, Allen R, Bertelsen S, Evans W, Dick D, Rice J, et al. Functional variant in a bitter-taste receptor (hTAS2R16) influences risk of alcohol dependence. Am J Hum Genet. 2006;78(1):103–111. doi: 10.1086/499253. PubMed DOI PMC

Wang JC, Hinrichs AL, Bertelsen S, Stock H, Budde JP, Dick DM, Bucholz KK, Rice J, Saccone N, Edenberg HJ, et al. Functional variants in TAS2R38 and TAS2R16 influence alcohol consumption in high-risk families of African-American origin. Alcohol Clin Exp Res. 2007;31(2):209–215. doi: 10.1111/j.1530-0277.2006.00297.x. PubMed DOI

Mangold JE, Payne TJ, Ma JZ, Chen G, Li MD. Bitter taste receptor gene polymorphisms are an important factor in the development of nicotine dependence in African Americans. J Med Genet. 2008;45(9):578–582. doi: 10.1136/jmg.2008.057844. PubMed DOI

Behrens M, Meyerhof W. Oral and extraoral bitter taste receptors. Results Probl Cell Differ. 2010;52:87–99. doi: 10.1007/978-3-642-14426-4_8. PubMed DOI

Clark AA, Liggett SB, Munger SD. Extraoral bitter taste receptors as mediators of off-target drug effects. FASEB J. 2012;26(12):4827–4831. doi: 10.1096/fj.12-215087. PubMed DOI PMC

Rozengurt E, Sternini C. Taste receptor signaling in the mammalian gut. Curr Opin Pharmacol. 2007;7(6):557–562. doi: 10.1016/j.coph.2007.10.002. PubMed DOI PMC

Sternini C. Taste receptors in the gastrointestinal tract. IV. Functional implications of bitter taste receptors in gastrointestinal chemosensing. Am J Physiol Gastrointest Liver Physiol. 2007;292(2):G457–G461. doi: 10.1152/ajpgi.00411.2006. PubMed DOI

Bufe B, Hofmann T, Krautwurst D, Raguse JD, Meyerhof W. The human TAS2R16 receptor mediates bitter taste in response to beta-glucopyranosides. Nat Genet. 2002;32(3):397–401. doi: 10.1038/ng1014. PubMed DOI

Vane JR. The fight against rheumatism: from willow bark to COX-1 sparing drugs. J Physiol Pharmacol. 2000;51(4 Pt 1):573–586. PubMed

Singh Ranger G. The role of aspirin in colorectal cancer chemoprevention. Crit Rev Oncol Hematol. 2016;104:87–90. doi: 10.1016/j.critrevonc.2016.05.011. PubMed DOI

Hua X, Phipps AI, Burnett-Hartman AN, Adams SV, Hardikar S, Cohen SA, Kocarnik JM, Ahnen DJ, Lindor NM, Baron JA, et al. Timing of aspirin and other nonsteroidal anti-inflammatory drug use among patients with colorectal cancer in relation to tumor markers and survival. J Clin Oncol. 2017. JCO.2017.2072.3569. PubMed PMC

Campbell MC, Ranciaro A, Zinshteyn D, Rawlings-Goss R, Hirbo J, Thompson S, Woldemeskel D, Froment A, Rucker JB, Omar SA, et al. Origin and differential selection of allelic variation at TAS2R16 associated with salicin bitter taste sensitivity in Africa. Mol Biol Evol. 2014;31(2):288–302. doi: 10.1093/molbev/mst211. PubMed DOI PMC

Kupcinskas J, Bruzaite I, Juzenas S, Gyvyte U, Jonaitis L, Kiudelis G, Skieceviciene J, Leja M, Pauzas H, Tamelis A, et al. Lack of association between miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608 gene polymorphisms and colorectal cancer. Sci Rep. 2014;4:5993. doi: 10.1038/srep05993. PubMed DOI PMC

Kupcinskas J, Gyvyte U, Bruzaite I, Leja M, Kupcinskaite-Noreikiene R, Pauzas H, Tamelis A, Jonaitis L, Skieceviciene J, Kiudelis G. Common genetic variants of PSCA, MUC1 and PLCE1 genes are not associated with colorectal cancer. Asian Pac J Cancer Prev. 2015;16(14):6027–6032. doi: 10.7314/APJCP.2015.16.14.6027. PubMed DOI

Moreno V, Gemignani F, Landi S, Gioia-Patricola L, Chabrier A, Blanco I, Gonzalez S, Guino E, Capella G, Canzian F. Polymorphisms in genes of nucleotide and base excision repair: risk and prognosis of colorectal cancer. Clin Cancer Res. 2006;12(7 Pt 1):2101–2108. doi: 10.1158/1078-0432.CCR-05-1363. PubMed DOI

Barrett JC, Fry B, Maller J, Daly MJ. Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics. 2005;21(2):263–265. doi: 10.1093/bioinformatics/bth457. PubMed DOI

Boyle AP, Hong EL, Hariharan M, Cheng Y, Schaub MA, Kasowski M, Karczewski KJ, Park J, Hitz BC, Weng S, et al. Annotation of functional variation in personal genomes using RegulomeDB. Genome Res. 2012;22(9):1790–1797. doi: 10.1101/gr.137323.112. PubMed DOI PMC

Ward LD, Kellis M. HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants. Nucleic Acids Res. 2012;40(Database issue):D930–D934. doi: 10.1093/nar/gkr917. PubMed DOI PMC

Consortium G. The genotype-tissue expression (GTEx) project. Nat Genet. 2013;45(6):580–585. doi: 10.1038/ng.2653. PubMed DOI PMC

Choi JH, Lee J, Choi IJ, Kim YW, Ryu KW, Kim J. Variations in TAS1R taste receptor gene family modify food intake and gastric cancer risk in a Korean population. Mol Nutr Food Res. 2016;60(11):2433–2445. doi: 10.1002/mnfr.201600145. PubMed DOI

Choi JH, Lee J, Choi IJ, Kim YW, Ryu KW, Kim J. Genetic variation in the TAS2R38 bitter taste receptor and gastric cancer risk in Koreans. Sci Rep. 2016;6:26904. doi: 10.1038/srep26904. PubMed DOI PMC