title: Genetic variation of Cytochrome P450 1B1 (CYP1B1) and risk of breast cancer among Polish women.
abstract: Four single nucleotide polymorphisms (SNPs) in CYP1B1 (Ex2 + 143 C > G, Ex2 + 356 G > T, Ex3 + 251 G > C, Ex3 + 315 A > G) cause amino acid changes (R48G, A119S, L432V and N453S, respectively) and are associated with increased formation of catechol estrogens; however, epidemiologic evidence only weakly supports an association between these variants and breast cancer risk. Because genetic variability conferring increased susceptibility could exist beyond these putative functional variants, we comprehensively examined the common genetic variability within CYP1B1. A total of eight haplotype-tagging (ht)SNPs (including Ex3 + 315 A > G), in addition to two putatively functional SNPs (Ex2 + 143 C > G and Ex3 + 251 G > C), were selected and genotyped in a large case-control study of Polish women (1995 cases and 2296 controls). Haplotypes were estimated using the expectation-maximization algorithm, and overall differences in the haplotype distribution between cases and controls were assessed using a global score test. We also evaluated levels of tumor CYP1B1 protein expression in a subset of 841 cases by immunohistochemistry, and their association with genetic variants. In the Polish population, we observed two linkage disequilibrium (LD)-defined blocks. Neither haplotypes (global P-value of 0.99 and 0.67 for each block of LD, respectively), nor individual SNPs (including three putatively functional SNPs) were associated with breast cancer risk. CYP1B1 was expressed in most tumor tissues (98%), and the level of expression was not related to the studied genetic variants. We found little evidence for modification of the estimated effect of haplotypes or individual SNPs by age, family history of breast cancer, or tumor hormone receptor status. The present study provides strong evidence against the existence of a substantial overall association between common genetic variation in CYP1B1 and breast cancer risk.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, Bethesda, Maryland 20852, USA. gaudetm@mail.nih.gov
authors.forename: Mia M
authors.initials: MM
authors.lastname: Gaudet
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Sonja I
authors.initials: SI
authors.lastname: Berndt
authors.forename: Xiaohong Rose
authors.initials: XR
authors.lastname: Yang
authors.forename: Beata
authors.initials: B
authors.lastname: Peplonska
authors.forename: Louise A
authors.initials: LA
authors.lastname: Brinton
authors.forename: Robert
authors.initials: R
authors.lastname: Welch
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Alicja
authors.initials: A
authors.lastname: Bardin-Mikolajczak
authors.forename: Mark E
authors.initials: ME
authors.lastname: Sherman
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Sutter
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
mesh_terms: D000328:Adult; D000368:Aged; D001189:Aryl Hydrocarbon Hydroxylases; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D065633:Cytochrome P-450 CYP1B1; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D005260:Female; D014644:Genetic Variation; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D011044:Poland; D020641:Polymorphism, Single Nucleotide; D012307:Risk Factors
chemical_list: D003577:Cytochrome P-450 Enzyme System; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D065633:Cytochrome P-450 CYP1B1