Genome-wide association study identifies a novel breast cancer susceptibility locus at 6q25.1

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Abstract

A genome-wide association study was conducted among Chinese women to identify risk variants for breast cancer. By analyzing 607,728 SNPs in 1505 cases and 1522 controls, we selected 29 promising SNPs for a fast-track replication in an independent set of 1554 cases and 1576 controls. Four replicated loci were further investigated in a third set of samples including 3472 cases and 900 controls. SNP rs2046210 at 6q25.1, located upstream of the estrogen receptor 1 gene ( ESR1), exhibited strong and consistent association with breast cancer across all three stages. Adjusted odds ratio (95% CI) were 1.36 (1.24–1.49) and 1.59 (1.40–1.82), respectively, for genotypes A/G and A/A versus G/G (P for trend, 2.0×10 ⁻¹⁵) in the pooled analysis of samples from all three stages. A similar, although weaker, association was also found in an independent study including 1591 cases and 1466 controls of European ancestry (P _trend, 0.01). These results provide strong evidence implicating 6q25.1 as a susceptibility locus for breast cancer.

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Most cited references 19

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A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.

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We conducted a genome-wide association study (GWAS) of breast cancer by genotyping 528,173 SNPs in 1,145 postmenopausal women of European ancestry with invasive breast cancer and 1,142 controls. We identified four SNPs in intron 2 of FGFR2 (which encodes a receptor tyrosine kinase and is amplified or overexpressed in some breast cancers) that were highly associated with breast cancer and confirmed this association in 1,776 affected individuals and 2,072 controls from three additional studies. Across the four studies, the association with all four SNPs was highly statistically significant (P(trend) for the most strongly associated SNP (rs1219648) = 1.1 x 10(-10); population attributable risk = 16%). Four SNPs at other loci most strongly associated with breast cancer in the initial GWAS were not associated in the replication studies. Our summary results from the GWAS are available online in a form that should speed the identification of additional risk loci.

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Reproductive and hormonal factors are involved in the etiology of breast cancer, but there are only a few prospective studies on endogenous sex hormone levels and breast cancer risk. We reanalyzed the worldwide data from prospective studies to examine the relationship between the levels of endogenous sex hormones and breast cancer risk in postmenopausal women. We analyzed the individual data from nine prospective studies on 663 women who developed breast cancer and 1765 women who did not. None of the women was taking exogenous sex hormones when their blood was collected to determine hormone levels. The relative risks (RRs) for breast cancer associated with increasing hormone concentrations were estimated by conditional logistic regression on case-control sets matched within each study. Linear trends and heterogeneity of RRs were assessed by two-sided tests or chi-square tests, as appropriate. The risk for breast cancer increased statistically significantly with increasing concentrations of all sex hormones examined: total estradiol, free estradiol, non-sex hormone-binding globulin (SHBG)-bound estradiol (which comprises free and albumin-bound estradiol), estrone, estrone sulfate, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone sulfate, and testosterone. The RRs for women with increasing quintiles of estradiol concentrations, relative to the lowest quintile, were 1.42 (95% confidence interval [CI] = 1.04 to 1.95), 1.21 (95% CI = 0.89 to 1.66), 1.80 (95% CI = 1.33 to 2.43), and 2.00 (95% CI = 1.47 to 2.71; P(trend)<.001); the RRs for women with increasing quintiles of free estradiol were 1.38 (95% CI = 0.94 to 2.03), 1.84 (95% CI = 1.24 to 2.74), 2.24 (95% CI = 1.53 to 3.27), and 2.58 (95% CI = 1.76 to 3.78; P(trend)<.001). The magnitudes of risk associated with the other estrogens and with the androgens were similar. SHBG was associated with a decrease in breast cancer risk (P(trend) =.041). The increases in risk associated with increased levels of all sex hormones remained after subjects who were diagnosed with breast cancer within 2 years of blood collection were excluded from the analysis. Levels of endogenous sex hormones are strongly associated with breast cancer risk in postmenopausal women.

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Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 6 January 2009

Publication date (Electronic): 15 February 2009

Publication date (Print): March 2009

Publication date PMC-release: 30 September 2009

Volume: 41

Issue: 3

Pages: 324-328

Affiliations

[1 ]Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, Tennessee

[2 ]Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China

[3 ]Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, Tennessee

[4 ]Shanghai Center for Disease Prevention and Control, Shanghai Institute of Preventive Medicine, Shanghai, China

[5 ]Department of Biomedical Informatics, Vanderbilt University School of Medicine, Nashville, Tennessee

[6 ]Center for Human Genetics Research, Vanderbilt University School of Medicine, Nashville, Tennessee

[7 ]Meharry Medical College, School of Medicine, Nashville, Tennessee

Author notes

Corresponding author contact information: Wei Zheng, Vanderbilt Epidemiology Center, Institute of Medicine & Public Health, Vanderbilt University Medical Center, 2525 West End Avenue, 8 ^th Floor, Nashville, TN 37203-1738, Phone: (615) 936-0682, Fax: (615) 936-8241, E-mail: wei.zheng@ 123456vanderbilt.edu

Author Contribution: WZ directed the study and drafted the manuscript along with JL, QC, and XOS. JL coordinated the study and managed the genotyping data. QC directed the lab operation. JL, CL, and WW performed statistical analyses. WZ directed the SBCS and the NBHS, and XOS directed the SBCSS and the SECS, the four parent studies. YTG, YBX, and WL directed the data and sample collection of SBCS, SBCSS and SECS in Shanghai. YZ and KG supervised data and sample collection. SLD and AMF coordinated the NBHS. SL directed Stage I genotyping. CL, SL, and JLH contributed to manuscript revision. All authors have reviewed and approved the final manuscript.

Article

Manuscript ID: nihpa85992

DOI: 10.1038/ng.318

PMC ID: 2754845

PubMed ID: 19219042

SO-VID: ee727d31-e45b-4e75-8784-8b7e0f8f95c8