Cancer Causes & Control

, Volume 23, Issue 9, pp 1429–1442 | Cite as

Effects of phenotypes in heterocyclic aromatic amine (HCA) metabolism–related genes on the association of HCA intake with the risk of colorectal adenomas

  • Aline Barbir
  • Jakob Linseisen
  • Silke Hermann
  • Rudolf Kaaks
  • Birgit Teucher
  • Monika Eichholzer
  • Sabine Rohrmann
Original paper



Heterocyclic aromatic amines (HCA), formed by high-temperature cooking of meat, are well-known risk factors for colorectal cancer (CRC). Enzymes metabolizing HCAs may influence the risk of CRC depending on the enzyme activity level. We aimed to assess effect modification by polymorphisms in the HCA-metabolizing genes on the association of HCA intake with colorectal adenoma (CRA) risk, which are precursors of CRC.


A case–control study nested in the EPIC-Heidelberg cohort was conducted. Between 1994 and 2005, 413 adenoma cases were identified and 796 controls were matched to cases. Genotypes were determined and used to predict phenotypes (i.e., enzyme activities). Odds ratios (OR) and corresponding 95 % confidence intervals (CI) were calculated by logistic regression analysis.


CRA risk was positively associated with PhIP, MeIQx, and DiMeIQx (p trend = 0.006, 0.022, and 0.045, respectively) intake. SULT1A1 phenotypes modified the effect of MeIQx on CRA risk (p Interaction > 0.01) such that the association of MeIQx intake with CRA was stronger for slow than for normal phenotypes. Other modifying effects by phenotypes did not reach statistical significance.


HCA intake is positively associated with CRA risk, regardless of phenotypes involved in the metabolizing process. Due to the number of comparisons made in the analysis, the modifying effect of SULT1A1 on the association of HCA intake with CRA risk may be due to chance.


Colorectal adenoma Genetic polymorphisms Phenotypes Heterocyclic aromatic amines 



This study was granted by the Kurt-Eberhard-Bode Foundation.

Conflict of interest

The authors declare that they have no conflict of interest.


  1. 1.
    Boyle P, Ferlay J (2005) Cancer incidence and mortality in Europe, 2004. Ann Oncol 16(3):481–488. doi: 10.1093/annonc/mdi098 PubMedCrossRefGoogle Scholar
  2. 2.
    Chan DS, Lau R, Aune D, Vieira R, Greenwood DC, Kampman E, Norat T (2011) Red and processed meat and colorectal cancer incidence: meta-analysis of prospective studies. PLoS One 6(6):e20456. doi: 10.1371/journal.pone.0020456 PubMedCrossRefGoogle Scholar
  3. 3.
    Sinha R (2002) An epidemiologic approach to studying heterocyclic amines. Mutat Res 506–507:197–204PubMedGoogle Scholar
  4. 4.
    Sinha R, Norat T (2002) Meat cooking and cancer risk. IARC Sci Publ 156:181–186PubMedGoogle Scholar
  5. 5.
    Murkovic M (2004) Formation of heterocyclic aromatic amines in model systems. J Chromatogr B Analyt Technol Biomed Life Sci 802(1):3–10. doi: 10.1016/j.jchromb.2003.09.026 PubMedCrossRefGoogle Scholar
  6. 6.
    Strickland PT, Qian Z, Friesen MD, Rothman N, Sinha R (2002) Metabolites of 2-amino-1-methyl-6-phenylimidazo(4,5-b)pyridine (PhIP) in human urine after consumption of charbroiled or fried beef. Mutat Res 506–507:163–173PubMedGoogle Scholar
  7. 7.
    Skog KI, Johansson MA, Jagerstad MI (1998) Carcinogenic heterocyclic amines in model systems and cooked foods: a review on formation, occurrence and intake. Food Chem Toxicol 36(9–10):879–896PubMedGoogle Scholar
  8. 8.
    Zheng W, Lee SA (2009) Well-done meat intake, heterocyclic amine exposure, and cancer risk. Nutr Cancer 61(4):437–446. doi: 10.1080/01635580802710741 PubMedCrossRefGoogle Scholar
  9. 9.
    Shirai T, Tamano S, Sano M, Masui T, Hasegawa R, Ito N (1995) Carcinogenicity of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) in rats: dose-response studies. Princess Takamatsu Symp 23:232–239PubMedGoogle Scholar
  10. 10.
    Adamson RH, Snyderwine EG, Thorgeirsson UP, Schut HA, Turesky RJ, Thorgeirsson SS, Takayama S, Sugimura T (1990) Metabolic processing and carcinogenicity of heterocyclic amines in nonhuman primates. Princess Takamatsu Symp 21:289–301PubMedGoogle Scholar
  11. 11.
    Risio M (2010) The natural history of adenomas. Best Pract Res Clin Gastroenterol 24(3):271–280. doi: 10.1016/j.bpg.2010.04.005 PubMedCrossRefGoogle Scholar
  12. 12.
    Sinha R, Kulldorff M, Chow WH, Denobile J, Rothman N (2001) Dietary intake of heterocyclic amines, meat-derived mutagenic activity, and risk of colorectal adenomas. Cancer Epidemiol Biomarkers Prev 10(5):559–562PubMedGoogle Scholar
  13. 13.
    Ishibe N, Sinha R, Hein DW, Kulldorff M, Strickland P, Fretland AJ, Chow WH, Kadlubar FF, Lang NP, Rothman N (2002) Genetic polymorphisms in heterocyclic amine metabolism and risk of colorectal adenomas. Pharmacogenetics 12(2):145–150PubMedCrossRefGoogle Scholar
  14. 14.
    Tiemersma EW, Voskuil DW, Bunschoten A, Hogendoorn EA, Witteman BJ, Nagengast FM, Glatt H, Kok FJ, Kampman E (2004) Risk of colorectal adenomas in relation to meat consumption, meat preparation, and genetic susceptibility in a Dutch population. Cancer Causes Control 15(3):225–236. doi: 10.1023/B:CACO.0000024263.44973.92 PubMedCrossRefGoogle Scholar
  15. 15.
    Gunter MJ, Probst-Hensch NM, Cortessis VK, Kulldorff M, Haile RW, Sinha R (2005) Meat intake, cooking-related mutagens and risk of colorectal adenoma in a sigmoidoscopy-based case-control study. Carcinogenesis 26(3):637–642. doi: 10.1093/carcin/bgh350 PubMedCrossRefGoogle Scholar
  16. 16.
    Sinha R, Peters U, Cross AJ, Kulldorff M, Weissfeld JL, Pinsky PF, Rothman N, Hayes RB (2005) Meat, meat cooking methods and preservation, and risk for colorectal adenoma. Cancer Res 65(17):8034–8041. doi: 10.1158/0008-5472.CAN-04-3429 PubMedGoogle Scholar
  17. 17.
    Wu K, Giovannucci E, Byrne C, Platz EA, Fuchs C, Willett WC, Sinha R (2006) Meat mutagens and risk of distal colon adenoma in a cohort of U.S. men. Cancer Epidemiol Biomarkers Prev 15(6):1120–1125. doi: 10.1158/1055-9965.EPI-05-0782 PubMedCrossRefGoogle Scholar
  18. 18.
    Shin A, Shrubsole MJ, Ness RM, Wu H, Sinha R, Smalley WE, Shyr Y, Zheng W (2007) Meat and meat-mutagen intake, doneness preference and the risk of colorectal polyps: the Tennessee Colorectal Polyp Study. Int J Cancer 121(1):136–142. doi: 10.1002/ijc.22664 PubMedCrossRefGoogle Scholar
  19. 19.
    Shin A, Shrubsole MJ, Rice JM, Cai Q, Doll MA, Long J, Smalley WE, Shyr Y, Sinha R, Ness RM, Hein DW, Zheng W (2008) Meat intake, heterocyclic amine exposure, and metabolizing enzyme polymorphisms in relation to colorectal polyp risk. Cancer Epidemiol Biomarkers Prev 17(2):320–329. doi: 10.1158/1055-9965.EPI-07-0615 PubMedCrossRefGoogle Scholar
  20. 20.
    Martinez ME, Jacobs ET, Ashbeck EL, Sinha R, Lance P, Alberts DS, Thompson PA (2007) Meat intake, preparation methods, mutagens and colorectal adenoma recurrence. Carcinogenesis 28(9):2019–2027. doi: 10.1093/carcin/bgm179 PubMedCrossRefGoogle Scholar
  21. 21.
    Rohrmann S, Hermann S, Linseisen J (2009) Heterocyclic aromatic amine intake increases colorectal adenoma risk: findings from a prospective European cohort study. Am J Clin Nutr 89(5):1418–1424. doi: 10.3945/ajcn.2008.26658 PubMedCrossRefGoogle Scholar
  22. 22.
    Ferrucci LM, Sinha R, Graubard BI, Mayne ST, Ma X, Schatzkin A, Schoenfeld PS, Cash BD, Flood A, Cross AJ (2009) Dietary meat intake in relation to colorectal adenoma in asymptomatic women. Am J Gastroenterol 104(5):1231–1240. doi: 10.1038/ajg.2009.102 PubMedCrossRefGoogle Scholar
  23. 23.
    Wang H, Yamamoto JF, Caberto C, Saltzman B, Decker R, Vogt TM, Yokochi L, Chanock S, Wilkens LR, Le Marchand L (2010) Genetic variation in the bioactivation pathway for polycyclic hydrocarbons and heterocyclic amines in relation to risk of colorectal neoplasia. Carcinogenesis 32(2):203–209. doi: 10.1093/carcin/bgq237 PubMedCrossRefGoogle Scholar
  24. 24.
    Rushmore TH, Kong AN (2002) Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes. Curr Drug Metab 3(5):481–490PubMedCrossRefGoogle Scholar
  25. 25.
    Sinha R, Rothman N, Brown ED, Mark SD, Hoover RN, Caporaso NE, Levander OA, Knize MG, Lang NP, Kadlubar FF (1994) Pan-fried meat containing high levels of heterocyclic aromatic amines but low levels of polycyclic aromatic hydrocarbons induces cytochrome P4501A2 activity in humans. Cancer Res 54(23):6154–6159PubMedGoogle Scholar
  26. 26.
    Turesky RJ (2004) The role of genetic polymorphisms in metabolism of carcinogenic heterocyclic aromatic amines. Curr Drug Metab 5(2):169–180PubMedCrossRefGoogle Scholar
  27. 27.
    Eichholzer M, Rohrmann S, Barbir A, Hermann S, Teucher B, Kaaks R, Linseisen J (2012) Polymorphisms in heterocyclic aromatic amines metabolism-related genes are associated with colorectal adenoma risk. Int J Mol Epidemiol Gen (accepted)Google Scholar
  28. 28.
    Ferrucci LM, Cross AJ, Gunter MJ, Ahn J, Mayne ST, Ma X, Chanock SJ, Yeager M, Graubard BI, Berndt SI, Huang WY, Hayes RB, Sinha R (2010) Xenobiotic metabolizing genes, meat-related exposures, and risk of advanced colorectal adenoma. World Rev Nutr Diet 101:34–45. doi: 10.1159/000314509 PubMedCrossRefGoogle Scholar
  29. 29.
    Hainaut P, Vozar B, Rinaldi S, Riboli E, Caboux E (2011) The European prospective investigation into cancer and nutrition biobank. Methods Mol Biol 675:179–191. doi: 10.1007/978-1-59745-423-0_7 PubMedCrossRefGoogle Scholar
  30. 30.
    Riboli E, Hunt KJ, Slimani N, Ferrari P, Norat T, Fahey M, Charrondiere UR, Hemon B, Casagrande C, Vignat J, Overvad K, Tjonneland A, Clavel-Chapelon F, Thiebaut A, Wahrendorf J, Boeing H, Trichopoulos D, Trichopoulou A, Vineis P, Palli D, Bueno-De-Mesquita HB, Peeters PH, Lund E, Engeset D, Gonzalez CA, Barricarte A, Berglund G, Hallmans G, Day NE, Key TJ, Kaaks R, Saracci R (2002) European Prospective Investigation into Cancer and Nutrition (EPIC): study populations and data collection. Public Health Nutr 5(6B):1113–1124. doi: 10.1079/PHN2002394 PubMedCrossRefGoogle Scholar
  31. 31.
    Bohlscheid-Thomas S, Hoting I, Boeing H, Wahrendorf J (1997) Reproducibility and relative validity of food group intake in a food frequency questionnaire developed for the German part of the EPIC project. European Prospective Investigation into Cancer and Nutrition. Int J Epidemiol 26(Suppl 1):S59–S70PubMedCrossRefGoogle Scholar
  32. 32.
    Rohrmann S, Zoller D, Hermann S, Linseisen J (2007) Intake of heterocyclic aromatic amines from meat in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heidelberg cohort. Br J Nutr 98(6):1112–1115PubMedCrossRefGoogle Scholar
  33. 33.
    Skog K, Augustsson K, Steineck G, Stenberg M, Jagerstad M (1997) Polar and non-polar heterocyclic amines in cooked fish and meat products and their corresponding pan residues. Food Chem Toxicol 35(6):555–565PubMedCrossRefGoogle Scholar
  34. 34.
    Sinha R, Rothman N, Salmon CP, Knize MG, Brown ED, Swanson CA, Rhodes D, Rossi S, Felton JS, Levander OA (1998) Heterocyclic amine content in beef cooked by different methods to varying degrees of doneness and gravy made from meat drippings. Food Chem Toxicol 36(4):279–287PubMedCrossRefGoogle Scholar
  35. 35.
    Nordmark A, Lundgren S, Ask B, Granath F, Rane A (2002) The effect of the CYP1A2 *1F mutation on CYP1A2 inducibility in pregnant women. Br J Clin Pharmacol 54(5):504–510PubMedCrossRefGoogle Scholar
  36. 36.
    Butler LM, Duguay Y, Millikan RC, Sinha R, Gagne JF, Sandler RS, Guillemette C (2005) Joint effects between UDP-glucuronosyltransferase 1A7 genotype and dietary carcinogen exposure on risk of colon cancer. Cancer Epidemiol Biomarkers Prev 14(7):1626–1632. doi: 10.1158/1055-9965.EPI-04-0682 PubMedCrossRefGoogle Scholar
  37. 37.
    Engelke CE, Meinl W, Boeing H, Glatt H (2000) Association between functional genetic polymorphisms of human sulfotransferases 1A1 and 1A2. Pharmacogenetics 10(2):163–169PubMedCrossRefGoogle Scholar
  38. 38.
    Magagnotti C, Pastorelli R, Pozzi S, Andreoni B, Fanelli R, Airoldi L (2003) Genetic polymorphisms and modulation of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP)-DNA adducts in human lymphocytes. Int J Cancer 107(6):878–884. doi: 10.1002/ijc.11492 PubMedCrossRefGoogle Scholar
  39. 39.
    Yamanaka H, Nakajima M, Katoh M, Hara Y, Tachibana O, Yamashita J, McLeod HL, Yokoi T (2004) A novel polymorphism in the promoter region of human UGT1A9 gene (UGT1A9*22) and its effects on the transcriptional activity. Pharmacogenetics 14(5):329–332PubMedCrossRefGoogle Scholar
  40. 40.
    Hein DW, Doll MA, Fretland AJ, Leff MA, Webb SJ, Xiao GH, Devanaboyina US, Nangju NA, Feng Y (2000) Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms. Cancer Epidemiol Biomarkers Prev 9(1):29–42PubMedGoogle Scholar
  41. 41.
    Le Marchand L, Hankin JH, Pierce LM, Sinha R, Nerurkar PV, Franke AA, Wilkens LR, Kolonel LN, Donlon T, Seifried A, Custer LJ, Lum-Jones A, Chang W (2002) Well-done red meat, metabolic phenotypes and colorectal cancer in Hawaii. Mutat Res 506–507:205–214PubMedGoogle Scholar
  42. 42.
    Cotterchio M, Boucher BA, Manno M, Gallinger S, Okey AB, Harper PA (2008) Red meat intake, doneness, polymorphisms in genes that encode carcinogen-metabolizing enzymes, and colorectal cancer risk. Cancer Epidemiol Biomarkers Prev 17(11):3098–3107. doi: 10.1158/1055-9965.EPI-08-0341 PubMedCrossRefGoogle Scholar
  43. 43.
    Lilla C, Risch A, Verla-Tebit E, Hoffmeister M, Brenner H, Chang-Claude J (2007) SULT1A1 genotype and susceptibility to colorectal cancer. Int J Cancer 120(1):201–206. doi: 10.1002/ijc.22156 PubMedCrossRefGoogle Scholar
  44. 44.
    Turesky RJ, Vouros P (2004) Formation and analysis of heterocyclic aromatic amine-DNA adducts in vitro and in vivo. J Chromatogr B Analyt Technol Biomed Life Sci 802(1):155–166. doi: 10.1016/j.jchromb.2003.10.053 PubMedCrossRefGoogle Scholar
  45. 45.
    Nguyen TV, Janssen MJ, van Oijen MG, Bergevoet SM, te Morsche RH, van Asten H, Laheij RJ, Peters WH, Jansent JB (2010) Genetic polymorphisms in GSTA1, GSTP1, GSTT1, and GSTM1 and gastric cancer risk in a Vietnamese population. Oncol Res 18(7):349–355PubMedCrossRefGoogle Scholar
  46. 46.
    Sweeney C, Coles BF, Nowell S, Lang NP, Kadlubar FF (2002) Novel markers of susceptibility to carcinogens in diet: associations with colorectal cancer. Toxicology 181–182:83–87PubMedCrossRefGoogle Scholar
  47. 47.
    Turesky RJ, Le Marchand L (2011) Metabolism and biomarkers of heterocyclic aromatic amines in molecular epidemiology studies: lessons learned from aromatic amines. Chem Res Toxicol 24(8):1169–1214. doi: 10.1021/tx200135s PubMedCrossRefGoogle Scholar
  48. 48.
    Tijhuis MJ, Wark PA, Aarts JM, Visker MH, Nagengast FM, Kok FJ, Kampman E (2005) GSTP1 and GSTA1 polymorphisms interact with cruciferous vegetable intake in colorectal adenoma risk. Cancer Epidemiol Biomarkers Prev 14(12):2943–2951. doi: 10.1158/1055-9965.EPI-05-0591 PubMedCrossRefGoogle Scholar
  49. 49.
    Skjelbred CF, Saebo M, Hjartaker A, Grotmol T, Hansteen IL, Tveit KM, Hoff G, Kure EH (2007) Meat, vegetables and genetic polymorphisms and the risk of colorectal carcinomas and adenomas. BMC Cancer 7:228. doi: 10.1186/1471-2407-7-228 PubMedCrossRefGoogle Scholar
  50. 50.
    Tiemersma EW, Wark PA, Ocke MC, Bunschoten A, Otten MH, Kok FJ, Kampman E (2003) Alcohol consumption, alcohol dehydrogenase 3 polymorphism, and colorectal adenomas. Cancer Epidemiol Biomarkers Prev 12(5):419–425PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2012

Authors and Affiliations

  • Aline Barbir
    • 1
  • Jakob Linseisen
    • 2
    • 3
  • Silke Hermann
    • 3
  • Rudolf Kaaks
    • 3
  • Birgit Teucher
    • 3
  • Monika Eichholzer
    • 1
  • Sabine Rohrmann
    • 1
    • 3
  1. 1.Division of Cancer Epidemiology and Prevention, Institute of Social and Preventive MedicineUniversity of ZurichZürichSwitzerland
  2. 2.Institute of Epidemiology IHelmholtz Zentrum MünchenNeuherbergGermany
  3. 3.German Cancer Research Center (DKFZ)HeidelbergGermany

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