title: Breast cancer: a candidate gene approach across the estrogen metabolic pathway.
abstract: Polymorphisms within the estrogen metabolic pathway are prime candidates for a possible association with breast cancer risk. We investigated 11 genes encoding key proteins of this pathway for their potential contribution to breast cancer risk. Of these CYP17A1, CYP19A1, EPHX1, HSD17B1, SRD5A2, and PPARG2 participate in biosynthesis, CYP1A1, CYP1B1, COMT, GSTP1, and SOD2 in catabolism and detoxification. We performed a population-based case-control study with 688 incident breast cancer cases and 724 controls from Germany and genotyped 18 polymorphisms by matrix assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), PCR based RFLP (restriction fragment length polymorphism), and TaqMan allelic discrimination. Genotype frequencies were compared between cases and controls and odds ratios were calculated by conditional logistic regression. Further statistical analyses were based on cluster analysis, multifactor dimensionality reduction, logic regression, and global testing. Single factor analyses pointed to CYP1B1_1294_GG as a possible breast cancer risk modulator (OR = 2.57; 95% CI: 1.34-4.93) and two way stratification suggested associations between BMI > or = 30 kg/m(2) and COMT_472_GG (P = 0.0076 and P = 0.0026), BMI < 20 kg/m(2) and HSD17B1_937_GG (P = 0.0082) as well as CYP17A1_-34_CC and HRT use > or =10 years (P = 0.0063). Following correction for multiple testing none of these associations remained significant. No significant association between breast cancer risk and genetic polymorphisms was observed in multifactor analyses. The tested polymorphisms of the estrogen metabolic pathway may not play a direct role in breast cancer risk. Therefore, future association studies should be extended to other polymorphisms and other regulatory pathways.
authors.affiliation: Molecular Mechanisms of Origin and Treatment of Breast Cancer, Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Auerbachstrasse 112, Stuttgart, Germany.
authors.forename: Christina
authors.initials: C
authors.lastname: Justenhoven
authors.forename: Ute
authors.initials: U
authors.lastname: Hamann
authors.forename: Falk
authors.initials: F
authors.lastname: Schubert
authors.forename: Marc
authors.initials: M
authors.lastname: Zapatka
authors.forename: Christiane B
authors.initials: CB
authors.lastname: Pierl
authors.forename: Sylvia
authors.initials: S
authors.lastname: Rabstein
authors.forename: Silvia
authors.initials: S
authors.lastname: Selinski
authors.forename: Tina
authors.initials: T
authors.lastname: Mueller
authors.forename: Katja
authors.initials: K
authors.lastname: Ickstadt
authors.forename: Michael
authors.initials: M
authors.lastname: Gilbert
authors.forename: Yon-Dschun
authors.initials: YD
authors.lastname: Ko
authors.forename: Christian
authors.initials: C
authors.lastname: Baisch
authors.forename: Beate
authors.initials: B
authors.lastname: Pesch
authors.forename: Volker
authors.initials: V
authors.lastname: Harth
authors.forename: Hermann M
authors.initials: HM
authors.lastname: Bolt
authors.forename: Caren
authors.initials: C
authors.lastname: Vollmert
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Roland
authors.initials: R
authors.lastname: Eils
authors.forename: Jürgen
authors.initials: J
authors.lastname: Dippon
authors.forename: Hiltrud
authors.initials: H
authors.lastname: Brauch
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D016022:Case-Control Studies; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D012150:Polymorphism, Restriction Fragment Length; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization
chemical_list: D014408:Biomarkers, Tumor; D004967:Estrogens