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Common Genetic Variation in GATA-Binding Protein 3 and Differential Susceptibility to Breast Cancer by Estrogen Receptor Tumor Status

¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland; ² Departments of Genetics and Pathology, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, North Carolina; ³ Core Genotyping Facility Advanced Technology Center, National Cancer Institute, Gaithersburg, Maryland; ⁴ Department of Genetics, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Centre and ⁵ Faculty of Medicine, University of Oslo, Oslo, Norway; ⁶ Cancer Center and M. Sklodowska Curie Institute of Oncology, Warsaw, Poland; ⁷ Nofer Institute of Occupational Medicine, Lodz, Poland; ⁸ Office of Cancer Genomics and ⁹ Pediatrics Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland; and ¹⁰ Institute of Community Medicine, University of Tromsø, Tromsø, Norway

Requests for reprints: Montserrat Garcia-Closas, Hormonal and Reproductive Epidemiology Branch Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Boulevard, Room 7076, MSC 7234, Rockville, MD 20852-7234. Phone: 301-435-3981; Fax: 301-402-0916. E-mail: montse{at}nih.gov

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 (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. (Cancer Epidemiol Biomarkers Prev 2007;16(11):2269–75)

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