Skip to main content
SpringerLink
Log in

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

  • Original paper
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  1. Boyle P, Ferlay J (2005) Cancer incidence and mortality in Europe, 2004. Ann Oncol 16(3):481–488. doi:10.1093/annonc/mdi098

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  3. Sinha R (2002) An epidemiologic approach to studying heterocyclic amines. Mutat Res 506–507:197–204

    PubMed  Google Scholar 

  4. Sinha R, Norat T (2002) Meat cooking and cancer risk. IARC Sci Publ 156:181–186

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 506–507:163–173

    PubMed  Google Scholar 

  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):879–896

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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 23:232–239

    PubMed  CAS  Google Scholar 

  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 21:289–301

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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):559–562

    PubMed  CAS  Google Scholar 

  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):145–150

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  24. Rushmore TH, Kong AN (2002) Pharmacogenomics, regulation and signaling pathways of phase I and II drug metabolizing enzymes. Curr Drug Metab 3(5):481–490

    Article  PubMed  CAS  Google Scholar 

  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):6154–6159

    PubMed  CAS  Google Scholar 

  26. Turesky RJ (2004) The role of genetic polymorphisms in metabolism of carcinogenic heterocyclic aromatic amines. Curr Drug Metab 5(2):169–180

    Article  PubMed  CAS  Google Scholar 

  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)

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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–S70

    Article  PubMed  Google Scholar 

  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):1112–1115

    Article  PubMed  CAS  Google Scholar 

  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):555–565

    Article  PubMed  CAS  Google Scholar 

  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):279–287

    Article  PubMed  CAS  Google Scholar 

  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):504–510

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  37. Engelke CE, Meinl W, Boeing H, Glatt H (2000) Association between functional genetic polymorphisms of human sulfotransferases 1A1 and 1A2. Pharmacogenetics 10(2):163–169

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):329–332

    Article  PubMed  CAS  Google Scholar 

  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):29–42

    PubMed  CAS  Google Scholar 

  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 506–507:205–214

    PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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):349–355

    Article  PubMed  Google Scholar 

  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 181–182:83–87

    Article  PubMed  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  CAS  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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):419–425

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

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

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Cancer Epidemiology and Prevention, Institute of Social and Preventive Medicine, University of Zurich, Hirschengraben 84, 8001, Zürich, Switzerland

    Aline Barbir, Monika Eichholzer & Sabine Rohrmann

  2. Institute of Epidemiology I, Helmholtz Zentrum München, Neuherberg, Germany

    Jakob Linseisen

  3. German Cancer Research Center (DKFZ), Heidelberg, Germany

    Jakob Linseisen, Silke Hermann, Rudolf Kaaks, Birgit Teucher & Sabine Rohrmann

Authors
  1. Aline Barbir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jakob Linseisen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Silke Hermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Rudolf Kaaks
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Birgit Teucher
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Monika Eichholzer
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Sabine Rohrmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Sabine Rohrmann.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Barbir, A., Linseisen, J., Hermann, S. et al. Effects of phenotypes in heterocyclic aromatic amine (HCA) metabolism–related genes on the association of HCA intake with the risk of colorectal adenomas. Cancer Causes Control 23, 1429–1442 (2012). https://doi.org/10.1007/s10552-012-0017-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-012-0017-8

Keywords

Search

Navigation