Digestive Diseases and Sciences

, Volume 53, Issue 5, pp 1417–1421

CYP1B1 Polymorphisms and K-ras Mutations in Patients with Pancreatic Ductal Adenocarcinoma

  • Marta Crous-Bou
  • Immaculata De Vivo
  • Miquel Porta
  • José A. Pumarega
  • Tomàs López
  • Joan Alguacil
  • Eva Morales
  • Núria Malats
  • Juli Rifà
  • David J. Hunter
  • Francisco X. Real
  • For the PANKRAS II Study Group
Original Paper


The frequency of CYP1B1 polymorphisms in pancreatic cancer has never been reported. There is also no evidence on the relationship between CYP1B1 variants and mutations in ras genes (K-, H- or N-ras) in any human neoplasm. We analyzed the following CYP1B1 polymorphisms in 129 incident cases of pancreatic ductal adenocarcinoma (PDA): the m1 allele (Val to Leu at codon 432) and the m2 allele (Asn to Ser at codon 453). The calculated frequencies for the m1 Val and m2 Asn alleles were 0.45 and 0.68, respectively. CYP1B1 genotypes were out of Hardy–Weinberg equilibrium; this was largely due to K-ras mutated PDA cases. The Val/Val genotype was over five times more frequent in PDA cases with a K-ras mutation than in wild-type cases (OR = 5.25; P = 0.121). In PDA, polymorphisms in CYP1B1 might be related with K-ras activation pathways.


Pancreatic neoplasms CYP1B1 polymorphisms K-ras oncogene ras genes 



Multicenter prospective study on the role of the K-ras and other genetic alterations in the diagnosis, prognosis, and etiology of pancreatic and biliary diseases


Pancreatic ductal adenocarcinoma


Cytochrome P450 1B1


Polycyclic aromatic hydrocarbons


Odds ratio


Confidence interval


  1. 1.
    Buters JT, Sakai S, Richter T, Pineau T, Alexander DL, Savas U, Doehmer J, Ward JM, Jefcoate CR, Gonzalez FJ (1999) Cytochrome P450 CYP1B1 determines susceptibility to 7, 12-dimethylbenz[a]anthracene-induced lymphomas. Proc Natl Acad Sci USA 96:1977–1982PubMedCrossRefGoogle Scholar
  2. 2.
    Badawi AF, Cavalieri EL, Rogan EG (2000) Effect of chlorinated hydrocarbons on expression of cytochrome P450 1A1, 1A2 and 1B1 and 2- and 4-hydroxylation of 17beta-estradiol in female Sprague-Dawley rats. Carcinogenesis 21:1593–1599PubMedCrossRefGoogle Scholar
  3. 3.
    Agundez JA (2004) Cytochrome P450 gene polymorphism and cancer. Curr Drug Metab 5:211–224PubMedCrossRefGoogle Scholar
  4. 4.
    Belous AR, Hachey DL, Dawling S, Roodi N, Parl FF (2007) Cytochrome P450 1B1-mediated estrogen metabolism results in estrogen-deoxyribonucleoside adduct formation. Cancer Res 67:812–817PubMedCrossRefGoogle Scholar
  5. 5.
    Nebert DW, Dalton TP (2006) The role of cytochrome P450 enzymes in endogenous signalling pathways and environmental carcinogenesis. Nat Rev Cancer 6:947–960PubMedCrossRefGoogle Scholar
  6. 6.
    Zheng W, Xie DW, Jin F, Cheng JR, Dai Q, Wen WQ, Shu XO, Gao YT (2000) Genetic polymorphism of cytochrome P450-1B1 and risk of breast cancer. Cancer Epidemiol Biomarkers Prev 9:147–150PubMedGoogle Scholar
  7. 7.
    Hung RJ, Boffetta P, Brennan P, Malaveille C, Hautefeuille A, Donato F, Gelatti U, Spaliviero M, Placidi D, Carta A, Scotto di Carlo A, Porru S (2004) GST, NAT, SULT1A1, CYP1B1 genetic polymorphisms, interactions with environmental exposures and bladder cancer risk in a high-risk population. Int J Cancer 110:598–604PubMedCrossRefGoogle Scholar
  8. 8.
    Wenzlaff AS, Cote ML, Bock CH, Land SJ, Santer SK, Schwartz DR, Schwartz AG (2005) CYP1A1 and CYP1B1 polymorphisms and risk of lung cancer among never smokers: a population-based study. Carcinogenesis 26:2207–2212PubMedCrossRefGoogle Scholar
  9. 9.
    Han W, Pentecost BT, Spivack SD (2003) Functional evaluation of novel single nucleotide polymorphisms and haplotypes in the promoter regions of CYP1B1 and CYP1A1 genes. Mol Carcinog 37:158–169PubMedCrossRefGoogle Scholar
  10. 10.
    Paracchini V, Raimondi S, Gram IT, Kang D, Kocabas NA, Kristensen VN, Li D, Parl FF, Rylander-Rudqvist T, Soucek P, Zheng W, Wedren S, Taioli E (2007) Meta- and pooled analyses of the cytochrome P-450 1B1 Val432Leu polymorphism and breast cancer: a HuGE-GSEC review. Am J Epidemiol 165:115–125PubMedCrossRefGoogle Scholar
  11. 11.
    Aklillu E, Oscarson M, Hidestrand M, Leidvik B, Otter C, Ingelman-Sundberg M (2002) Functional analysis of six different polymorphic CYP1B1 enzyme variants found in an Ethiopian population. Mol Pharmacol 61:586–594PubMedCrossRefGoogle Scholar
  12. 12.
    De Vivo I, Hankinson SE, Li L, Colditz GA, Hunter DJ (2002) Association of CYP1B1 polymorphisms and breast cancer risk. Cancer Epidemiol Biomarkers Prev 11: 489–492PubMedGoogle Scholar
  13. 13.
    McGrath M, Hankinson SE, Arbeitman L, Colditz GA, Hunter DJ, De Vivo I (2004) Cytochrome P450 1B1 and catechol-O-methyltransferase polymorphisms and endometrial cancer susceptibility. Carcinogenesis 25:559–565PubMedCrossRefGoogle Scholar
  14. 14.
    Rylander-Rudqvist T, Wedren S, Jonasdottir G, Ahlberg S, Weiderpass E, Persson I, Ingelman-Sundberg M (2004) Cytochrome P450 1B1 gene polymorphisms and postmenopausal endometrial cancer risk. Cancer Epidemiol Biomarkers Prev 13:1515–1520PubMedGoogle Scholar
  15. 15.
    Bailey L, Roodi N, Dupont W, Parl F (1998) Association of cytochrome P450 1B1 (CYP1B1) polymorphisms with steroid receptor status in breast cancer. Cancer Res 58:5038–5041PubMedGoogle Scholar
  16. 16.
    Weiderpass E, Partanen T, Kaaks R, Vainio H, Porta M, Kauppinen T et al (1999) Pancreatic cancer: occurrence, trends, and environmental etiology. A review. Scand J Work Environ Health 24:165–174Google Scholar
  17. 17.
    Ekbom A, Hunter D (2002) Pancreatic cancer. In: Adami HO, Hunter D, Trichopoulos D (eds) Textbook of cancer epidemiology. Oxford University Press, New York, pp 233–247Google Scholar
  18. 18.
    Hecht SS (2003) Tobacco carcinogens, their biomarkers and tobacco-induced cancer. Nat Rev Cancer 3:733–744PubMedCrossRefGoogle Scholar
  19. 19.
    Li D, Jiao L, Porta M (2005) Epidemiology. In: von Hoff DD, Evans DB, Hruban RH (eds) Pancreatic cancer. Jones & Bartlett, Boston, pp 103–117Google Scholar
  20. 20.
    Schuller HM (2002) Mechanisms of smoking-related lung and pancreatic adenocarcinoma development. Nat Rev Cancer 2:455–463PubMedCrossRefGoogle Scholar
  21. 21.
    Soliman AS, Bondy M, Webb CR et al (2006) Differing molecular pathology of pancreatic adenocarcinoma in Egyptian and United States patients. Int J Cancer 119:1455–1461PubMedCrossRefGoogle Scholar
  22. 22.
    Alguacil J, Porta M, Malats N, Kauppinen T, Kogevinas M, Benavides FG et al (2002) Occupational exposure to organic solvents and K-ras mutations in exocrine pancreatic cancer. Carcinogenesis 23:101–106PubMedCrossRefGoogle Scholar
  23. 23.
    Alguacil J, Porta M, Kauppinen T, Malats N, Kogevinas M, Carrato A (2003) Occupational exposure to dyes, metals, polycyclic aromatic hydrocarbons and other agents and K-ras activation in human exocrine pancreatic cancer. Int J Cancer 107:635–641PubMedCrossRefGoogle Scholar
  24. 24.
    Porta M, Malats N, Jariod M, Grimalt JO, Rifà J, Carrato A et al (1999) Serum concentrations of organochlorine compounds and K-ras mutations in exocrine pancreatic cancer. Lancet 354: 2125–2129PubMedCrossRefGoogle Scholar
  25. 25.
    Wark PA, Van der Kuil W, Ploemacher J, Van Muijen GN, Mulder CJ, Weijenberg MP et al (2006) Diet, lifestyle and risk of K-ras mutation-positive and -negative colorectal adenomas. Int J Cancer 119:398–405PubMedCrossRefGoogle Scholar
  26. 26.
    Porta M, Malats N, Guarner L, Carrato A, Rifà J, Salas A et al (1999) Association between coffee drinking and K-ras mutations in exocrine pancreatic cancer. J Epidemiol Community Health 53:702–709PubMedCrossRefGoogle Scholar
  27. 27.
    Porta M, Fabregat X, Malats N, Guarner L, Carrato A, de Miguel A et al (2005) Exocrine pancreatic cancer: symptoms at presentation and their relation to tumour site and stage. Clin Transl Oncol 7:189–197PubMedCrossRefGoogle Scholar
  28. 28.
    Armitage P, Berry G, Matthews JNS (2002) Statistical methods in medical research, 4th edn. Blackwell, OxfordGoogle Scholar
  29. 29.
    Kleinbaum DG, Kupper LL, Morgenstern H (1982) Epidemiologic research. Lifetime Learning Publications, Belmont, CA, pp 320–376, 343, 419–456Google Scholar
  30. 30.
    Li D, Firozi PF, Zhang W, Shen J, DiGiovanni J, Lau S, Evans D, Friess H, Hassan M, Abbruzzese JL (2002) DNA adducts, genetic polymorphisms, and K-ras mutation in human pancreatic cancer. Mutat Res 513:37–48PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2008

Authors and Affiliations

  • Marta Crous-Bou
    • 1
    • 2
  • Immaculata De Vivo
    • 3
    • 4
  • Miquel Porta
    • 1
    • 2
  • José A. Pumarega
    • 1
  • Tomàs López
    • 1
  • Joan Alguacil
    • 1
    • 5
  • Eva Morales
    • 1
  • Núria Malats
    • 1
  • Juli Rifà
    • 6
  • David J. Hunter
    • 3
    • 4
  • Francisco X. Real
    • 1
    • 7
  • For the PANKRAS II Study Group
  1. 1.Institut Municipal d’Investigació Mèdica (IMIM)CIBER de Epidemiología y Salud Pública (CIBERESP)BarcelonaSpain
  2. 2.School of MedicineUniversitat Autònoma de BarcelonaBarcelonaSpain
  3. 3.Harvard School of Public HealthBostonUSA
  4. 4.Channing LaboratoryBrigham and Women’s HospitalBostonUSA
  5. 5.Department of Environmental Biology & Public HealthUniversidad de HuelvaHuelvaSpain
  6. 6.Hospital Son DuretaPalma de MallorcaSpain
  7. 7.Universitat Pompeu FabraBarcelonaSpain

Personalised recommendations