title: Common genetic variation in GATA-binding protein 3 and differential susceptibility to breast cancer by estrogen receptor alpha tumor status.
abstract: GATA-binding protein 3 (GATA3) is a transcription factor and a putative tumor suppressor that is highly expressed in normal breast luminal epithelium and estrogen receptor alpha (ER)-positive breast tumors. We hypothesized that common genetic variation in GATA3 could influence breast carcinogenesis. Four tag single-nucleotide polymorphisms (SNP) in GATA3 and its 3' flanking gene FLJ4598 were genotyped in two case control studies in Norway and Poland (2,726 cases and 3,420 controls). Analyses of pooled data suggested a reduced risk of breast cancer associated with two intronic variants in GATA3 in linkage disequilibrium (rs3802604 in intron 3 and rs570613 in intron 4). Odds ratio (95% confidence interval) for rs570613 heterozygous and rare homozygous versus common homozygous were 0.85 (0.75-1.95) and 0.82 (0.62-0.96), respectively (P(trend)=0.004). Stronger associations were observed for subjects with ER-negative, than ER-positive, tumors (P(heterogeneity)=0.01 for rs3802604; P(heterogeneity)=0.09 for rs570613). Although no individual SNPs were associated with ER-positive tumors, two haplotypes (GGTC in 2% of controls and AATT in 7% of controls) showed significant and consistent associations with increased risk for these tumors when compared with the common haplotype (GATT in 46% of controls): 1.71 (1.27-2.32) and 1.26 (1.03-1.54), respectively. In summary, data from two independent study populations showed two intronic variants in GATA3 associated with overall decreases in breast cancer risk and suggested heterogeneity of these associations by ER status. These differential associations are consistent with markedly different levels of GATA3 protein by ER status. Additional epidemiologic studies are needed to clarify these intriguing relationships.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Boulevard, Room 7076, MSC 7234, Rockville, MD 20852-7234, USA. montse@nih.gov
authors.forename: Montserrat
authors.initials: M
authors.lastname: Garcia-Closas
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Troester
authors.forename: Ying
authors.initials: Y
authors.lastname: Qi
authors.forename: Anita
authors.initials: A
authors.lastname: Langerød
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Jolanta
authors.initials: J
authors.lastname: Lissowska
authors.forename: Louise
authors.initials: L
authors.lastname: Brinton
authors.forename: Robert
authors.initials: R
authors.lastname: Welch
authors.forename: Beata
authors.initials: B
authors.lastname: Peplonska
authors.forename: Daniela S
authors.initials: DS
authors.lastname: Gerhard
authors.forename: Inger Torhild
authors.initials: IT
authors.lastname: Gram
authors.forename: Vessela
authors.initials: V
authors.lastname: Kristensen
authors.forename: Anne-Lise
authors.initials: AL
authors.lastname: Børresen-Dale
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Charles M
authors.initials: CM
authors.lastname: Perou
mesh_terms: D000328:Adult; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D005260:Female; D050990:GATA3 Transcription Factor / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008593:Menopause; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011980:Receptors, Progesterone / Q000235:genetics
chemical_list: D047628:Estrogen Receptor alpha; D050990:GATA3 Transcription Factor; C494749:GATA3 protein, human; D011980:Receptors, Progesterone