Abstract
Using an Affymetrix 10K SNP array to screen for gene copy number changes in breast cancer, we detected a single-gene amplification of the ESR1 gene, which encodes estrogen receptor alpha, at 6q25. A subsequent tissue microarray analysis of more than 2,000 clinical breast cancer samples showed ESR1 amplification in 20.6% of breast cancers. Ninety-nine percent of tumors with ESR1 amplification showed estrogen receptor protein overexpression, compared with 66.6% cancers without ESR1 amplification (P < 0.0001). In 175 women who had received adjuvant tamoxifen monotherapy, survival was significantly longer for women with cancer with ESR1 amplification than for women with estrogen receptor–expressing cancers without ESR1 amplification (P = 0.023). Notably, we also found ESR1 amplification in benign and precancerous breast diseases, suggesting that ESR1 amplification may be a common mechanism in proliferative breast disease and a very early genetic alteration in a large subset of breast cancers.
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Acknowledgements
We thank the University Medical Center Hamburg Eppendorf for providing an outstanding environment for research. We are grateful to S. Schnöger, A. Blaszczyk-Wewer, G. Rieck, M. Sachs, S. Schmidt, M. Härtling and M. Mirlacher for technical support.
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Contributions
F.H., P.R.S. and C.R. produced the ESR1 FISH probes, performed FISH analysis and contributed to the writing of the paper; Z.J. contributed to FISH analysis; M.W. and F.H. performed amplicon mapping; F.H. and O.H. performed qPCR analysis; A.L. and L.T. performed estrogen receptor immunohistochemistry analysis; F.J. contributed to data analysis and interpretation; K.A.-K. and G.S. selected tissues and performed histological diagnosis and R.S. and G.S. designed the study and contributed to the writing of the paper.
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The University Medical Center Hamburg-Eppendorf has filed a patent application for certain technology described in the paper.
Supplementary information
Supplementary Table 1
Prevalence of coamplifications involving ESR1 in breast cancer. (PDF 46 kb)
Supplementary Table 2
Contribution of potential prognostic factors to tumor-specific survival in breast cancer patients who received Tamoxifen monotherapy (multivariate COX regression mode). (PDF 41 kb)
Supplementary Table 3
Primers and probes used. (PDF 31 kb)
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Holst, F., Stahl, P., Ruiz, C. et al. Estrogen receptor alpha (ESR1) gene amplification is frequent in breast cancer. Nat Genet 39, 655–660 (2007). https://doi.org/10.1038/ng2006
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DOI: https://doi.org/10.1038/ng2006
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