Incidence of inactive allele CYP2D6*4 among Greek women suffering from hormone-sensitive breast cancer

Background: The incidence of CYP2D6*4 among Caucasians is estimated up to 27%, while it is present in up to 90% of all poor metabolizers within the Caucasian population. The hypothesis under question is whether the presence of one or two non-functioning (null) alleles predicts an inferior outcome in postmenopausal women with breast cancer receiving adjuvant treatment with tamoxifen. The aim of the present study is to estimate the incidence of CYP2D6*4, in the Greek population and more precisely among females suffering from breast cancer. Materials and Methods: Eighty unrelated mainland Greek female volunteers suffering from hormone-sensitive breast cancer were recruited during their primary handling or follow-up examination in order to provide samples for purification and polymerase chain reaction/ restriction fragment length polymorphism (PCR-RFLP) of genomic DNA derived from buccal swabs. Results: The incidence of individuals with at least one present allele*4 within the Hellenic population was estimated to be as high as 30% (n = 24/80), with a 95% confidence interval of 20% to 40%. From the statistical point of view, it can be securely stated that incidence of *4 among Greek women is over 20%. The incidence of homozygous carriers of *4 in the present sample occurred in 8.75%, while the incidence of allele*4 haplotype occurred in 19.4% (n=160). Conclusion: Although the outcoming results for Greek women are actually in line with existing data for other European nations, it should be noted, that a routine CYP2D6 testing of women suffering from breast cancer is formally not recommended, as the clinical significance of CYP2D6 phenotype in treatment and outcome of breast cancer remains unclear.

CYP2D6*4; Breast cancer; Tamoxifen; Caucasian.

[1] Zanger U.M., Raimundo S., Eichelbaum M.: “Cytochrome P450 2D6: overview and update on pharmacology, genetics, biochemistry”. Naunyn. Schmiedebergs Arch. Pharmacol., 2004, 369, 23.

[2] Droll K., Bruce-Mensah K., Otton S.V., Gaedigk A., Sellers E.M., Tyndale R.F.: “Comparison of three CYP2D6 probe substrates and genotype in Ghanaians, Chinese and Caucasians”. Pharmacogenetics, 1998, 8, 325.

[3] Marez D., Legrand M., Sabbagh N., Lo Guidice J.M., Spire C., Lafitte J.J., et al.: “Polymorphism of the cytochrome P450

CYP2D6 gene in a European population: characterization of 48 mutations and 53 alleles, their frequencies and evolution”. Pharmacogenetics, 1997, 7, 193.

[4] Sachse C., Brockmöller J., Bauer S., Roots I.: “Cytochrome P450 2D6 variants in a Caucasian population: allele frequencies and phenotypic consequences”. Am. J. Hum. Genet., 1997, 60, 284.

[5] Bernard S., Neville K.A., Nguyen A.T., Flockhart D.A.: “Interethnic differences in genetic polymorphisms of CYP2D6 in the U.S. population: clinical implications”. Oncologist, 2006, 11, 126.

[6] Frank D., Jaehde U., Fuhr U.: “Evaluation of probe drugs and pharmacokinetic metrics for CYP2D6 phenotyping”. Eur. J. Clin. Pharmacol.,2007, 63, 321.

[7] Lyon E., Gastier Foster J., Palomaki G.E., Pratt V.M., Reynolds K., Sábato M.F., et al.: “Laboratory Quality Assurance Committee., Laboratory testing of CYP2D6 alleles in relation to tamoxifen therapy”.Genet. Med., 2012, 14, 990.

[8] Zackrisson A.L., Holmgren P., Gladh A.B., Ahlner J., Lindblom B.: “Fatal intoxication cases: cytochrome P450 2D6 and 2C19 genotype distributions”. Eur. J. Clin. Pharmacol., 2004, 60, 547.

[9] Yamada H., Dahl M.L., Lannfelt L., Viitanen M., Winblad B.,Sjöqvist F.: “CYP2D6 and CYP2C19 genotypes in an elderly

Swedish population”. Eur. J. Clin. Pharmacol., 1998, 54, 479.

[10] Gawronska-Szklarz B., Wójcicki M., Kuprianowicz A., Kedzierska K., Kedzierski M., Górnik W., Pawlik A.: “CYP2D6 and GSTM1 genotypes in a Polish population”. Eur. J. Clin. Pharmacol., 1999, 55, 389.

[11] Niewinski P., Orzechowska-Juzwenko K., Hurkacz M., RzemislawskaZ., Jaźwinska- Tarnawska E., Milejski P., Forkasiewicz Z.: “CYP2D6 extensive, intermediate, and poor phenotypes and genotypes in a Polish population”. Eur. J. Clin. Pharmacol., 2002, 58,533.

[12] Buzková H., Pechandová K., Slanar O., Perlík F.: “Frequency of single nucleotide polymorphisms of CYP2D6 in the Czech population”. Cell. Biochem. Funct., 2008, 26, 76.

[13] Marandi T., Dahl M.L., Kiivet R.A., Rägo L., Sjöqvist F.: “Debrisoquin and S-mephenytoin hydroxylation phenotypes and

CYP2D6 genotypes in an Estonian population”. Pharmacol. Toxicol., 1996, 78, 303.

[14] Griese E.U., Zanger U.M., Brudermanns U., Gaedigk A., Mikus G., Mörike K., et al.: “Assessment of the predictive power of genotypes for the in-vivo catalytic function of CYP2D6 in a German population”. Pharmacogenetics, 1998, 8, 15.

[15] Tefre T., Daly A.K., Armstrong M., Leathart J.B., Idle J.R., Brøgger A., Børresen A.L.: “Genotyping of the CYP2D6 gene in Norwegian lung cancer patients and controls”. Pharmacogenetics, 1994, 4, 47.

[16] Tamminga W.J., Wemer J., Oosterhuis B., de Zeeuw R.A., de Leij L.F., Jonkman J.H.: “The prevalence of CYP2D6 and CYP2C19 genotypes in a population of healthy Dutch volunteers”. Eur. J. Clin. Pharmacol., 2001, 57, 717.

[17] Marandi T., Dahl M.L., Rägo L., Kiivet R., Sjöqvist F.: “Debrisoquine and S-mephenytoin hydroxylation polymorphisms in a Russian population living in Estonia”. Eur. J. Clin. Pharmacol., 1997, 53, 257.

[18] Gaikovitch E.A., Cascorbi I., Mrozikiewicz P.M., Brockmöller J., Frötschl R., Köpke K., et al.: “Polymorphisms of drug-metabolizing enzymes CYP2C9, CYP2C19, CYP2D6, CYP1A1, NAT2 and of Pglycoprotein in a Russian population”. Eur. J. Clin. Pharmacol., 2003, 59, 303.

[19] Bathum L., Andersen-Ranberg K., Boldsen J., Brøsen K., Jeune B.:“Genotypes for the cytochrome P450 enzymes CYP2D6 and CYP2C19 in human longevitY. Role of CYP2D6 and CYP2C19 in longevity”. Eur. J. Clin. Pharmacol., 1998, 54, 427.

[20] Madsen H., Nielsen K.K., Brøsen K.: “Imipramine metabolism in relation to the sparteine and mephenytoin oxidation polymorphisms--a population study”. Br. J. Clin. Pharmacol., 1995, 39, 433.

[21] Arvanitidis K., Ragia G., Iordanidou M., Kyriaki S., Xanthi A., Tavridou A., Manolopoulos V.G.: “Genetic polymorphisms of drugmetabolizing enzymes CYP2D6, CYP2C9, CYP2C19 and CYP3A5in the Greek population”. Fundam. Clin. Pharmacol., 2007, 21, 419.

[22] Falzoi M., Pira L., Lazzari P., Pani L.: “Analysis of CYP2D6 Allele Frequencies and Identification of Novel SNPs and Sequence Variations in Sardinians”. ISRN Genetics, 2013. Available at: http://www.hindawi.com/journals/isrn/2013/204560/

[23] Scordo M.G., Caputi A.P., D'Arrigo C., Fava G., Spina E.: “Allele and genotype frequencies of CYP2C9, CYP2C19 and CYP2D6 in an Italian population”. Pharmacol. Res., 2004, 50, 195.

[24] Laforest L., Wikman H., Benhamou S., Saarikoski S.T., Bouchardy C., Hirvonen A., et al.: “CYP2D6 gene polymorphism in caucasian smokers: lung cancer susceptibility and phenotype-genotype relationships”. Eur. J. Cancer, 2000, 36, 1825.

[25] Sabbagh N., Brice A., Marez D., Dürr A., Legrand M., Lo Guidice J.M., et al.: “CYP2D6 polymorphism and Parkinson's disease susceptibility”. Mov. Disord., 1999, 14, 230.

[26] Topić E., Stefanović M., Ivanisević A.M., Petrinović R., Curcić I.: “The cytochrome P450 2D6 (CYP2D6) gene polymorphism among breast and head and neck cancer patients”. Clin. Chim. Acta, 2000, 296, 101.

[27] Bozina N., Granić P., Lalić Z., Tramisak I., Lovrić M., Stavljenić- Rukavina A.: “Genetic polymorphisms of cytochromes P450: CYP2C9, CYP2C19, and CYP2D6 in Croatian population”. Croat. Med. J., 2003, 44, 425.

[28] Agúndez J.A., Jiménez-Jiménez F.J., Tejeda R., Ledesma M.C., Ortí- Pareja M., Gasalla T., et al.: “CYP2D6 polymorphism is not associated with essential tremor”. Eur. Neurol., 1997, 38, 99.

[29] Menoyo A., del Rio E., Baiget M.: “Characterization of variant alleles of cytochrome CYP2D6 in a Spanish population”. Cell. Biochem. Funct., 2006, 24, 381.

[30] Crescenti A., Mas S, Gassó P., Baiget M., Bernardo M., Lafuente A.: “Simultaneous genotyping of CYP2D6*3, *4, *5 and *6 polymorphisms in a Spanish population through multiplex long polymerase chain reaction and minisequencing multiplex single base extension analysis”. Clin. Exp. Pharmacol. Physiol., 2007, 34, 992.

[31] Hirvonen A., Husgafvel-Pursiainen K., Anttila S., Karjalainen A., Pelkonen O., Vainio H.: “PCR-based CYP2D6 genotyping for Finnish lung cancer patients”. Pharmacogenetics, 1993, 3, 19.

[32] Saarikoski S.T., Sata F., Husgafvel-Pursiainen K., Rautalahti M., Haukka J., Impivaara O., et al.: “CYP2D6 ultrarapid metabolizer genotype as a potential modifier of smoking behaviour”. Pharmacogenetics, 2000, 10, 5.

[33] Sistonen J., Sajantila A., Lao O., Corander J., Barbujani G., FuselliS.: “CYP2D6 worldwide genetic variation shows high frequency of altered activity variants and no continental structure”. Pharmacogenet.Genomics, 2007, 17, 93.

[34] Fuselli S., Dupanloup I., Frigato E., Cruciani F., Scozzari R., Moral P., et al.: “Molecular diversity at the CYP2D6 locus in the Mediterranean region”. Eur. J. Hum. Genet., 2004, 12, 916.

[35] Bonanni B., Macis D., Maisonneuve P., Johansson H.A., Gucciardo G., Oliviero P., et al.: “Polymorphism in the CYP2D6 tamoxifenmetabolizing gene influences clinical effect but not hot flashes: data from the Italian Tamoxifen Trial”. J. Clin. Oncol., 2006, 24, 3708.

[36] Fernández- Santander A., del Saz Sánchez M., Tejerina Gómez A.,Bandrés Moya F.: “CYP2D6*4 allele and breast cancer risk: is there any association?” Clin. Transl. Oncol., 2012, 14, 157.

[37] Ladona M.G., Abildúa R.E., Ladero J.M., Román J.M., Plaza M.A., Agúndez J.A., et al.: “CYP2D6 genotypes in Spanish women with breast cancer”. Cancer Lett., 1996, 99, 23.

[38] Markopoulos C., Kykalos S., Mantas D.: “Impact of CYP2D*6 in the adjuvant treatment of breast cancer patients with tamoxifen”. World J. Clin. Oncol., 2014, 10, 374.

[39] Wegman P., Vainikka L., Stål O., Nordenskjöld B., Skoog L., Rutqvist L.E., Wingren S.: “Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer,patients”. Breast Cancer Res., 2005, 7, R284-R290.

[40] Wegman P., Elingarami S., Carstensen J., Stål O., Nordenskjöld B.,Wingren S.: “Genetic variants of CYP3A5, CYP2D6, SU LT1A1,UGT2B15 and tamoxifen response in postmenopausal patients with breast cancer”. Breast Cancer Res., 2007, 9, R7.

[41] Nowell S.A., Ahn J., Rae J.M., Scheys J.O., Trovato A., Sweeney C., MacLeod S.L., et al.: “Association of genetic variation in tamoxifen- metabolizing enzymes with overall survival and recurrence of disease in breast cancer patients”. Breast Cancer Res. Treat., 2005, 91, 249.

[42] Goetz M.P., Rae J.M., Suman V.J., Safgren S.L., Ames M.M., Visscher D.W., et al.: “Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes”. J. Clin. Oncol., 2005, 23, 9312.

[43] Goetz M.P., Knox S.K., Suman V.J., Rae J.M., Safgren S.L., Ames M.M., et al.: “The impact of cytochrome P450 2D6 metabolism in women receiving adjuvant tamoxifen”. Breast Cancer Res. Treat., 2007, 101, 113.

[44] Gonzalez-Santiago S., Zárate R., Haba-Rodríguez J., Gmez A., Bandrs E., Moreno P., et al.: “CYP2D64 polymorphism as blood predictivebiomarker of breast cancer relapse in patients receiving adjuvant tamoxifen (abstract 590)”. J. Clin. Oncol., 2007, 25, 590.

[45] Bijl M.J., van Schaik R.H., Lammers L.A., Hofman A., Vulto A.G., van Gelder T., et al.: “The CYP2D6*4 polymorphism affects breast cancersurvival in tamoxifen users”. Breast Cancer Res. Treat., 2009, 118, 125.

[46] Zafra-Ceres M., de Haro T., Farez-Vidal E., Blancas I., Bandres F., de Dueñas E.M., et al.: “Influence of CYP2D6 polymorphisms on serum levels of tamoxifen metabolites in Spanish women with breast cancer”. Int. J. Med. Sci., 2013, 10, 932.

[47] Irvin W.J., Walko C.M., Weck K.E., Ibrahim J.G., Chiu W.K., Dees E.C., et al.: “Genotype-guided tamoxifen dosing increases active metabolite exposure in women with reduced CYP2D6 metabolism: a multicenter study”. J. Clin. Oncol., 2011, 29, 3232.

[48] Abraham J.E., Maranian M.J., Driver K.E., Platte R., KalmyrzaevB., Baynes C., et al.: “CYP2D6 gene variants: association w ith breast cancer specific survival in a cohort of breast cancer patients from the United Kingdom treated with adjuvant tamoxifen”. Breast Cancer Res., 2010, 12, R64. [49] Sideras K., Ingle J.N., Ames M.M., Loprinzi C.L., Mrazek D.P., Black J.L., et al.: “Coprescription of tamoxifen and medications that inhibit CYP2D6”. J. Clin. Oncol., 2010, 28, 2768.

[50] Foley K.M.: “Advances in cancer pain management in 2005”. Gynecol. Oncol., 2005, 99, S126.

[51] Kalra S.P.: “Mandatory neuropeptide-steroid signaling for the preovulatory luteinizing hormone-releasing hormone discharge”. Endocr. Rev., 1993, 14, 507.